rs148915045

Positions:

chr14-23397060-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_002471.4(MYH6):c.2071G>A(p.Val691Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000434 in 1,614,194 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 4.72

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 -12 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=0.011579096).

BP6

Variant 14-23397060-C-T is Benign according to our data. Variant chr14-23397060-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164242.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr14-23397060-C-T is described in Lovd as [Benign]. Variant chr14-23397060-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00259 (395/152312) while in subpopulation AFR AF= 0.00917 (381/41564). AF 95% confidence interval is 0.00841. There are 2 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.2071G>A	p.Val691Ile	missense_variant	18/39	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.2071G>A	p.Val691Ile	missense_variant	18/39	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

395

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00919

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.00191

GnomAD3 exomes

AF:

0.000668

AC:

168

AN:

251440

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00747

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00259

AC:

395

AN:

152312

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00917

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00293

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000791

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2020	Variant summary: MYH6 c.2071G>A (p.Val691Ile) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 282834 control chromosomes, predominantly at a frequency of 0.0096 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 384 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (1x) and benign (3x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2015	p.Val691Ile in exon 18 of MYH6: This variant is not expected to have clinical si gnificance because it has been identified in 0.9% (92/10402) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs148915045). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2017	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 06, 2016

- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

MYH6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2018

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

0.29

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D

Eigen

Benign

0.056

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;.

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.83

N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.049

D;D

Polyphen

0.0010

B;B

Vest4

0.39

MVP

0.78

MPC

0.31

ClinPred

0.028

GERP RS

4.1

Varity_R

0.27

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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