chr14-23387914-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002471.4(MYH6):c.4369G>A(p.Glu1457Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 7.38

Publications

9 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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

BS2

High AC in GnomAdExome4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH6	NM_002471.4	MANE Select	c.4369G>A	p.Glu1457Lys	missense	Exon 31 of 39	NP_002462.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH6	ENST00000405093.9	TSL:5 MANE Select	c.4369G>A	p.Glu1457Lys	missense	Exon 31 of 39	ENSP00000386041.3
MYH6	ENST00000968262.1		c.4402G>A	p.Glu1468Lys	missense	Exon 31 of 39	ENSP00000638321.1
MYH6	ENST00000968257.1		c.4369G>A	p.Glu1457Lys	missense	Exon 31 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

248756

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000197

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1EE (1)

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 (1)

Hypertrophic cardiomyopathy 14 (1)

not provided (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.85

MutPred

0.75

Gain of methylation at E1457 (P = 0.0091)

MVP

0.97

MPC

0.88

ClinPred

0.97

GERP RS

4.4

Varity_R

0.51

gMVP

0.71

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over