ACTN2 : c.1714C>T

Variant Details

Variant (CDS)	Variant (protein)	Variant Type	Variant Effect	Genomic Location (GRCh37)	ExAC Frequency
c.1714C>T	p.R572W (Arg > Trp)	substitution	missense	chr1:236914827 (forward strand)	0.00004946

Effect in Cardiac Disease

This variant is considered a rare variant, with a population frequency of 0.00004946 (ExAC mean allelic frequency).

HCM	There is no significant excess of rare ACTN2 Non-Truncating variants in HCM (details). OMGL: Detected in 1 / 807 HCM patients - classified as Class 3-Unknown pathogenicity. LMM: Detected in 0 / 632 HCM patients.
DCM	There is no significant excess of rare ACTN2 Non-Truncating variants in DCM (details). OMGL: Detected in 0 / 305 DCM patients. LMM: Detected in 1 / 590 DCM patients - classified as VUS - 4.

HCM

There is no significant excess of rare ACTN2 Non-Truncating variants in HCM (details).

OMGL: Detected in 1 / 807 HCM patients - classified as Class 3-Unknown pathogenicity.

LMM: Detected in 0 / 632 HCM patients.

DCM

There is no significant excess of rare ACTN2 Non-Truncating variants in DCM (details).

OMGL: Detected in 0 / 305 DCM patients.

LMM: Detected in 1 / 590 DCM patients - classified as VUS - 4.

For more information on the clinical significance of this variant, please see the ClinVar entry.

Detection in Population Databases

Database	European	African	East Asian	South Asian	American	Finnish	Other	Total
ExAC	0.00000000 0 / 66700	0.00057770 6 / 10386	0.00000000 0 / 8648	0.00000000 0 / 16508	0.00000000 0 / 11566	0.00000000 0 / 6594	0.00000000 0 / 906	0.00004946 6 / 121308
ESP	0.00000 0 / 8600	0.00068 3 / 4406						0.00023 3 / 13006
1KG	0.00000 0 / 1006	0.00000 0 / 1322	0.00000 0 / 1008	0.00000 0 / 978	0.00000 0 / 694	0.00000 0 / 198		0.00000 0 / 5008

The Exome Aggregation Consortium (ExAC) is a database of 60,706 unrelated individuals sequenced as part of various disease-specific and population genetic studies. There is partial overlap between ExAC and 1000 Genomes (1KG) (1,851 of the 2,504 samples in 1KG) and the Exome Sequencing Project (ESP) (3,936 of the 6,500 samples in ESP).

Other Variant & Gene Details

Canonical Sequences
Transcript	ENST00000366578	LRG_436t1	NM_001103.2
Protein	ENSP00000355537	LRG_436p1		P35609

Missense Variant Predictions
SIFT	Grantham	Polyphen-DIV	Polyphen-VAR	Summary 75% of algorithms have predicted that this variant will adversely affect protein function
tolerated	moderately radical	probably damaging	probably damaging
LRT	MutationTaster	MutationAssessor	FATHMM
deleterious	disease-causing	medium impact	tolerated

References

1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.

3. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.