14-23386496-T-A

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.4778A>T(p.Gln1593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,108 control chromosomes in the GnomAD database, including 592 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 311 hom., cov: 31)

Exomes 𝑓: 0.0073 ( 281 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.99

Publications

5 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=0.0018672347).

BP6

Variant 14-23386496-T-A is Benign according to our data. Variant chr14-23386496-T-A is described in ClinVar as Benign. ClinVar VariationId is 44520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.4778A>T	p.Gln1593Leu	missense_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.4778A>T	p.Gln1593Leu	missense_variant	Exon 33 of 39	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5620

AN:

152076

Hom.:

311

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0166

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0113

AC:

2834

AN:

250484

AF XY:

0.00958

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.00800

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00317

Gnomad OTH exome

AF:

0.00915

GnomAD4 exome

AF:

0.00735

AC:

10728

AN:

1459914

Hom.:

281

Cov.:

AF XY:

0.00681

AC XY:

4943

AN XY:

726266

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.111

AC:

3666

AN:

32932

American (AMR)

AF:

0.00957

AC:

427

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26128

East Asian (EAS)

AF:

0.0124

AC:

492

AN:

39672

South Asian (SAS)

AF:

0.00632

AC:

544

AN:

86120

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00574

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00433

AC:

4810

AN:

1111002

Other (OTH)

AF:

0.0117

AC:

708

AN:

60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.351

Heterozygous variant carriers

541

1082

1623

2164

2705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.0370

AC:

5637

AN:

152194

Hom.:

311

Cov.:

AF XY:

0.0356

AC XY:

2650

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.118

AC:

4898

AN:

41484

American (AMR)

AF:

0.0144

AC:

221

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.0167

AC:

AN:

5164

South Asian (SAS)

AF:

0.00809

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00479

AC:

326

AN:

68004

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

228

456

685

913

1141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0131

Hom.:

Bravo

AF:

0.0429

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.0570

AC:

251

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.0149

AC:

1805

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Oct 24, 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. -

Dec 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Jul 08, 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

Benign

0.049

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.4

(source)

DANN

Benign

0.76

DEOGEN2

Uncertain

0.66

D;D

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.22

T;.

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

L;L

PhyloP100

2.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.22

Sift

Benign

0.82

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0

B;B

Vest4

0.089

MPC

0.25

ClinPred

0.0049

GERP RS

1.8

Varity_R

0.081

gMVP

0.33

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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