rs2277474

chr14-23405314-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002471.4(MYH6):c.411G>A(p.Glu137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,614,008 control chromosomes in the GnomAD database, including 48,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3915 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44921 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.342

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=-0.41).
• BP6: Variant 14-23405314-C-T is Benign according to our data. Variant chr14-23405314-C-T is described in ClinVar as [Benign]. Clinvar id is 44504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23405314-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.342 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.411G>A	p.Glu137=	synonymous_variant	5/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.411G>A	p.Glu137=	synonymous_variant	5/39	5	NM_002471.4	P1
MYH6	ENST00000557461.2	n.478G>A		non_coding_transcript_exon_variant	5/14	5

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33077 AN: 152074 Hom.: 3916 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.0561

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.207 AC: 52054 AN: 251464 Hom.: 6028 AF XY: 0.212 AC XY: 28754 AN XY: 135906

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.0561

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.243 AC: 354887 AN: 1461816 Hom.: 44921 Cov.: 59 AF XY: 0.242 AC XY: 175697 AN XY: 727210

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.0475

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.261

Gnomad4 OTH exome AF: 0.236

GnomAD4 genome AF: 0.217 AC: 33090 AN: 152192 Hom.: 3915 Cov.: 32 AF XY: 0.215 AC XY: 15962 AN XY: 74414

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.0564

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.221

Alfa AF: 0.247 Hom.: 6247

Bravo AF: 0.211

Asia WGS AF: 0.122 AC: 423 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.266

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

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	-0.41
Cadd	Benign	7.0
Dann	Benign	0.55

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: rs2277474; hg19: chr14-23874523; COSMIC: COSV62453843;