rs365990

Positions:

chr14-23392602-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.3302T>C(p.Val1101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,604,286 control chromosomes in the GnomAD database, including 113,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1101V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.44 ( 14788 hom., cov: 26)

Exomes 𝑓: 0.36 ( 98726 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.

BP4

Computational evidence support a benign effect (MetaRNN=3.2841323E-5).

BP6

Variant 14-23392602-A-G is Benign according to our data. Variant chr14-23392602-A-G is described in ClinVar as [Benign]. Clinvar id is 44480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23392602-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.3302T>C	p.Val1101Ala	missense_variant	25/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.3302T>C	p.Val1101Ala	missense_variant	25/39	5	NM_002471.4	ENSP00000386041	P1

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

63492

AN:

144438

Hom.:

14737

Cov.:

show subpopulations

Gnomad AFR

AF:

0.643

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.375

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.471

Gnomad NFE

AF:

0.374

Gnomad OTH

AF:

0.440

GnomAD3 exomes

AF:

0.337

AC:

84704

AN:

251460

Hom.:

15792

AF XY:

0.336

AC XY:

45686

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.454

Gnomad EAS exome

AF:

0.167

Gnomad SAS exome

AF:

0.310

Gnomad FIN exome

AF:

0.265

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.360

AC:

525544

AN:

1459746

Hom.:

98726

Cov.:

AF XY:

0.358

AC XY:

260255

AN XY:

726358

show subpopulations

Gnomad4 AFR exome

AF:

0.638

Gnomad4 AMR exome

AF:

0.245

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.149

Gnomad4 SAS exome

AF:

0.310

Gnomad4 FIN exome

AF:

0.272

Gnomad4 NFE exome

AF:

0.369

Gnomad4 OTH exome

AF:

0.373

GnomAD4 genome

AF:

0.440

AC:

63597

AN:

144540

Hom.:

14788

Cov.:

AF XY:

0.440

AC XY:

30482

AN XY:

69328

show subpopulations

Gnomad4 AFR

AF:

0.643

Gnomad4 AMR

AF:

0.375

Gnomad4 ASJ

AF:

0.462

Gnomad4 EAS

AF:

0.178

Gnomad4 SAS

AF:

0.313

Gnomad4 FIN

AF:

0.326

Gnomad4 NFE

AF:

0.374

Gnomad4 OTH

AF:

0.449

Alfa

AF:

0.382

Hom.:

29342

Bravo

AF:

0.433

TwinsUK

AF:

0.373

AC:

1383

ALSPAC

AF:

0.364

AC:

1403

ESP6500AA

AF:

0.616

AC:

2712

ESP6500EA

AF:

0.374

AC:

3214

ExAC

AF:

0.346

AC:

42017

Asia WGS

AF:

0.290

AC:

1008

AN:

3478

EpiCase

AF:

0.382

EpiControl

AF:

0.381

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 13, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 20062063, 20639392) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

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

0.061

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.33

T;.

MetaRNN

Benign

0.000033

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.67

PROVEAN

Benign

1.9

N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.022

MPC

0.42

ClinPred

0.0066

GERP RS

4.7

Varity_R

0.036

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over