Variant rs178640 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002471.4(MYH6):c.4914T>C(p.Ala1638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,613,716 control chromosomes in the GnomAD database, including 192,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22164 hom., cov: 32)

Exomes 𝑓: 0.48 ( 169992 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -4.26

Variant links:

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]

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 14-23386360-A-G is Benign according to our data. Variant chr14-23386360-A-G is described in ClinVar as [Benign]. Clinvar id is 44526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386360-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4914T>C	p.Ala1638=	synonymous_variant	33/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.4914T>C	p.Ala1638=	synonymous_variant	33/39	5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79940

AN:

151918

Hom.:

22117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.463

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.557

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.487

Gnomad FIN

AF:

0.479

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.473

Gnomad OTH

AF:

0.531

GnomAD3 exomes

AF:

0.452

AC:

113523

AN:

251072

Hom.:

27513

AF XY:

0.457

AC XY:

62065

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.712

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.546

Gnomad EAS exome

AF:

0.260

Gnomad SAS exome

AF:

0.491

Gnomad FIN exome

AF:

0.472

Gnomad NFE exome

AF:

0.476

Gnomad OTH exome

AF:

0.475

GnomAD4 exome

AF:

0.477

AC:

697292

AN:

1461678

Hom.:

169992

Cov.:

AF XY:

0.477

AC XY:

346925

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.713

Gnomad4 AMR exome

AF:

0.292

Gnomad4 ASJ exome

AF:

0.545

Gnomad4 EAS exome

AF:

0.279

Gnomad4 SAS exome

AF:

0.490

Gnomad4 FIN exome

AF:

0.465

Gnomad4 NFE exome

AF:

0.482

Gnomad4 OTH exome

AF:

0.481

GnomAD4 genome

AF:

0.526

AC:

80043

AN:

152038

Hom.:

22164

Cov.:

AF XY:

0.524

AC XY:

38926

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.704

Gnomad4 AMR

AF:

0.412

Gnomad4 ASJ

AF:

0.557

Gnomad4 EAS

AF:

0.268

Gnomad4 SAS

AF:

0.487

Gnomad4 FIN

AF:

0.479

Gnomad4 NFE

AF:

0.473

Gnomad4 OTH

AF:

0.536

Alfa

AF:

0.490

Hom.:

5985

Bravo

AF:

0.527

EpiCase

AF:

0.483

EpiControl

AF:

0.492

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 16, 2011	This variant is classified as benign because it does not change the amino acid a nd is frequent in the general population (rs178640, MAF >1%). -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 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

-0.88

CADD

Benign

0.10

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over