rs178640

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002471.4(MYH6):c.4914T>C(p.Ala1638Ala) 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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
Keppen-Lubinsky syndrome
Inheritance: AD Classification: MODERATE Submitted by: Illumina
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atrial septal defect 3
Inheritance: AD Classification: LIMITED Submitted by: G2P
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 44526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.4914T>C	p.Ala1638Ala	synonymous_variant	Exon 33 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 link	c.4914T>C	p.Ala1638Ala	synonymous_variant	Exon 33 of 39	5	NM_002471.4	ENSP00000386041.3		P13533

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

GnomAD2 exomes

AF:

0.452

AC:

113523

AN:

251072

AF XY:

0.457

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 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

African (AFR)

AF:

0.713

AC:

23868

AN:

33466

American (AMR)

AF:

0.292

AC:

13057

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

14250

AN:

26134

East Asian (EAS)

AF:

0.279

AC:

11077

AN:

39690

South Asian (SAS)

AF:

0.490

AC:

42269

AN:

86234

European-Finnish (FIN)

AF:

0.465

AC:

24812

AN:

53406

Middle Eastern (MID)

AF:

0.509

AC:

2911

AN:

5718

European-Non Finnish (NFE)

AF:

0.482

AC:

536032

AN:

1111944

Other (OTH)

AF:

0.481

AC:

29016

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

22010

44020

66029

88039

110049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15840

31680

47520

63360

79200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.526

AC:

80043

AN:

152038

Hom.:

22164

Cov.:

AF XY:

0.524

AC XY:

38926

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.704

AC:

29197

AN:

41484

American (AMR)

AF:

0.412

AC:

6293

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.557

AC:

1932

AN:

3470

East Asian (EAS)

AF:

0.268

AC:

1375

AN:

5130

South Asian (SAS)

AF:

0.487

AC:

2351

AN:

4826

European-Finnish (FIN)

AF:

0.479

AC:

5073

AN:

10580

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.473

AC:

32119

AN:

67948

Other (OTH)

AF:

0.536

AC:

1130

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1886

3772

5657

7543

9429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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%). -

May 17, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 14

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.65

PhyloP100

-4.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over