chr14-23390401-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.3388G>A(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,609,018 control chromosomes in the GnomAD database, including 7,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.089 ( 591 hom., cov: 31)

Exomes 𝑓: 0.12 ( 7186 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.899

Publications

24 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=0.0033628345).

BP6

Variant 14-23390401-C-T is Benign according to our data. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23390401-C-T is described in CliVar as Benign. Clinvar id is 44483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.3388G>A	p.Ala1130Thr	missense_variant	Exon 26 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.3388G>A	p.Ala1130Thr	missense_variant	Exon 26 of 39	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.0887

AC:

13458

AN:

151666

Hom.:

588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.0692

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0952

Gnomad EAS

AF:

0.0714

Gnomad SAS

AF:

0.0686

Gnomad FIN

AF:

0.0916

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.0947

AC:

23065

AN:

243682

AF XY:

0.0958

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.0950

Gnomad ASJ exome

AF:

0.0879

Gnomad EAS exome

AF:

0.0671

Gnomad FIN exome

AF:

0.0819

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.117

AC:

170393

AN:

1457236

Hom.:

7186

Cov.:

AF XY:

0.115

AC XY:

83702

AN XY:

724798

show subpopulations

African (AFR)

AF:

0.0221

AC:

737

AN:

33382

American (AMR)

AF:

0.0976

AC:

4339

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.0937

AC:

2444

AN:

26076

East Asian (EAS)

AF:

0.0752

AC:

2976

AN:

39568

South Asian (SAS)

AF:

0.0668

AC:

5743

AN:

85986

European-Finnish (FIN)

AF:

0.0806

AC:

4133

AN:

51258

Middle Eastern (MID)

AF:

0.109

AC:

617

AN:

5650

European-Non Finnish (NFE)

AF:

0.129

AC:

143357

AN:

1110588

Other (OTH)

AF:

0.100

AC:

6047

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

9032

18064

27096

36128

45160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5296

10592

15888

21184

26480

<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:

0.0887

AC:

13467

AN:

151782

Hom.:

591

Cov.:

AF XY:

0.0861

AC XY:

6389

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.0259

AC:

1073

AN:

41458

American (AMR)

AF:

0.109

AC:

1664

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

330

AN:

3468

East Asian (EAS)

AF:

0.0712

AC:

368

AN:

5172

South Asian (SAS)

AF:

0.0695

AC:

333

AN:

4790

European-Finnish (FIN)

AF:

0.0916

AC:

968

AN:

10566

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.124

AC:

8382

AN:

67808

Other (OTH)

AF:

0.119

AC:

249

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

563

1125

1688

2250

2813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.111

Hom.:

1275

Bravo

AF:

0.0906

TwinsUK

AF:

0.138

AC:

513

ALSPAC

AF:

0.129

AC:

499

ExAC

AF:

0.0910

AC:

11012

Asia WGS

AF:

0.0760

AC:

263

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Sep 30, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Benign based on high population frequency (rs28730771) -

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Cardiomyopathy

Benign:1

Nov 16, 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

Jul 15, 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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.050

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.46

T;.

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

M;M

PhyloP100

0.90

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.33

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.89

P;P

Vest4

0.47

MPC

2.8

ClinPred

0.037

GERP RS

3.4

Varity_R

0.033

gMVP

0.52

Mutation Taster

=86/14

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