rs145274612

chr14-23393501-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002471.4(MYH6):c.2946G>A(p.Glu982=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,126 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.00300

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 14-23393501-C-T is Benign according to our data. Variant chr14-23393501-C-T is described in ClinVar as [Benign]. Clinvar id is 44475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23393501-C-T is described in Lovd as [Benign]. Variant chr14-23393501-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00995 (1515/152274) while in subpopulation NFE AF= 0.0116 (789/68008). AF 95% confidence interval is 0.0109. There are 13 homozygotes in gnomad4. There are 810 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1515 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.2946G>A	p.Glu982=	synonymous_variant	23/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.2946G>A	p.Glu982=	synonymous_variant	23/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1515 AN: 152156 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0106 AC: 2668 AN: 251458 Hom.: 36 AF XY: 0.0104 AC XY: 1419 AN XY: 135906

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0107 AC: 15620 AN: 1461852 Hom.: 124 Cov.: 33 AF XY: 0.0104 AC XY: 7559 AN XY: 727218

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00581

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.0332

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00995 AC: 1515 AN: 152274 Hom.: 13 Cov.: 32 AF XY: 0.0109 AC XY: 810 AN XY: 74470

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0118 Hom.: 10

Bravo AF: 0.00731

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.00859

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2018	Variant summary: MYH6 c.2946G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 277200 control chromosomes in the gnomAD database, including 37 homozygotes. The observed variant frequency is approximately 439-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.2946G>A, has been reported in the literature in individuals affected with Cardiomyopathy (Posch_2011). This report does not provide an unequivocal conclusion about the association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2012	Glu982Glu in exon 23 of MYH6: This variant is classified as benign based on its high frequency in the general population (dbSNP rs145274612; NHLBI Exome Sequenc ing Project, http://evs.gs.washington.edu/EVS). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYH6: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	5.1
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145274612; hg19: chr14-23862710;