14-23407058-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.166G>A(p.Gly56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0774 in 1,614,154 control chromosomes in the GnomAD database, including 5,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G56G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.069 ( 398 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4897 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.70

Publications

27 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030651689).

BP6

Variant 14-23407058-C-T is Benign according to our data. Variant chr14-23407058-C-T is described in ClinVar as Benign. ClinVar VariationId is 44455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.166G>A	p.Gly56Arg	missense_variant	Exon 3 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.166G>A	p.Gly56Arg	missense_variant	Exon 3 of 39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000557461.2 link	n.233G>A		non_coding_transcript_exon_variant	Exon 3 of 14	5

Frequencies

GnomAD3 genomes

AF:

0.0695

AC:

10577

AN:

152192

Hom.:

397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0591

Gnomad AMI

AF:

0.0617

Gnomad AMR

AF:

0.0508

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.0140

Gnomad SAS

AF:

0.0779

Gnomad FIN

AF:

0.0500

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0847

Gnomad OTH

AF:

0.0810

GnomAD2 exomes

AF:

0.0683

AC:

17171

AN:

251470

AF XY:

0.0717

show subpopulations

Gnomad AFR exome

AF:

0.0559

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.0131

Gnomad FIN exome

AF:

0.0459

Gnomad NFE exome

AF:

0.0835

Gnomad OTH exome

AF:

0.0764

GnomAD4 exome

AF:

0.0783

AC:

114408

AN:

1461844

Hom.:

4897

Cov.:

AF XY:

0.0790

AC XY:

57449

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0604

AC:

2022

AN:

33478

American (AMR)

AF:

0.0429

AC:

1917

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2932

AN:

26136

East Asian (EAS)

AF:

0.00957

AC:

380

AN:

39700

South Asian (SAS)

AF:

0.0814

AC:

7024

AN:

86246

European-Finnish (FIN)

AF:

0.0490

AC:

2619

AN:

53412

Middle Eastern (MID)

AF:

0.0936

AC:

540

AN:

5768

European-Non Finnish (NFE)

AF:

0.0829

AC:

92134

AN:

1111986

Other (OTH)

AF:

0.0801

AC:

4840

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6546

13093

19639

26186

32732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3322

6644

9966

13288

16610

<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:

0.0694

AC:

10576

AN:

152310

Hom.:

398

Cov.:

AF XY:

0.0668

AC XY:

4976

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0590

AC:

2453

AN:

41566

American (AMR)

AF:

0.0506

AC:

774

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

361

AN:

3468

East Asian (EAS)

AF:

0.0139

AC:

AN:

5188

South Asian (SAS)

AF:

0.0780

AC:

376

AN:

4822

European-Finnish (FIN)

AF:

0.0500

AC:

531

AN:

10624

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0847

AC:

5760

AN:

68024

Other (OTH)

AF:

0.0806

AC:

170

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

518

1036

1555

2073

2591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0807

Hom.:

1649

Bravo

AF:

0.0691

TwinsUK

AF:

0.0839

AC:

311

ALSPAC

AF:

0.0802

AC:

309

ESP6500AA

AF:

0.0645

AC:

284

ESP6500EA

AF:

0.0883

AC:

759

ExAC

AF:

0.0698

AC:

8472

Asia WGS

AF:

0.0430

AC:

148

AN:

3476

EpiCase

AF:

0.0925

EpiControl

AF:

0.0900

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Feb 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

May 13, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:5

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23299917, 22429680, 27884173, 15998695, 33232181) -

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

- -

Cardiovascular phenotype

Benign:1

Jun 29, 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

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.9

H;H

PhyloP100

2.7

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.97

D;D

Vest4

0.17

MutPred

0.59

Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);

MPC

1.2

ClinPred

0.047

GERP RS

3.5

Varity_R

0.40

gMVP

0.76

Mutation Taster

=97/3

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