rs145274612

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002471.4(MYH6):c.2946G>A(p.Glu982Glu) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.00300

Publications

3 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 -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 VariationId is 44475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1515 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.2946G>A	p.Glu982Glu	synonymous_variant	Exon 23 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.2946G>A	p.Glu982Glu	synonymous_variant	Exon 23 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes

AF:

0.00996

AC:

1515

AN:

152156

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0106

AC:

2668

AN:

251458

AF XY:

0.0104

show subpopulations

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 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.:

AF XY:

0.0104

AC XY:

7559

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33478

American (AMR)

AF:

0.00581

AC:

260

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0313

AC:

817

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86252

European-Finnish (FIN)

AF:

0.0332

AC:

1771

AN:

53420

Middle Eastern (MID)

AF:

0.00401

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0107

AC:

11870

AN:

1112010

Other (OTH)

AF:

0.0106

AC:

638

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1015

2029

3044

4058

5073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.00995

AC:

1515

AN:

152274

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

810

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41550

American (AMR)

AF:

0.00889

AC:

136

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0365

AC:

387

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0116

AC:

789

AN:

68008

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0109

Hom.:

Bravo

AF:

0.00731

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.00859

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 27, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

May 29, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

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

- -

not provided

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH6: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypertrophic cardiomyopathy 14

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Feb 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Nov 18, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 18, 2014

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

-0.38

CADD

Benign

5.1

(source)

DANN

Benign

0.72

PhyloP100

-0.0030

Mutation Taster

=89/11

polymorphism

(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