rs727504739

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002471.4(MYH6):c.5062G>A(p.Glu1688Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.73

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.5062G>A	p.Glu1688Lys	missense_variant	Exon 34 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.5062G>A	p.Glu1688Lys	missense_variant	Exon 34 of 39	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Glu1688Lys variant in MYH6 has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Glu1688Lys variant may impact the normal function of the protein, though this information is not predictive enough to determine pathogenicity conclusively. Ad ditional information is needed to fully assess the clinical significance of the Glu1688Lys variant. -

Hypertrophic cardiomyopathy 14

Uncertain:1

Sep 18, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 179250). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 1688 of the MYH6 protein (p.Glu1688Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.5

H;H

PhyloP100

7.7

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.016

D;D

Sift4G

Benign

0.091

T;T

Polyphen

0.47

P;P

Vest4

0.65

MutPred

0.71

Gain of ubiquitination at E1688 (P = 0.0094);Gain of ubiquitination at E1688 (P = 0.0094);

MVP

0.87

MPC

0.72

ClinPred

0.98

GERP RS

4.2

Varity_R

0.39

gMVP

0.56

Mutation Taster

=26/74

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over