rs138206136

Positions:

chr17-10529949-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_017534.6(MYH2):c.2823G>T(p.Glu941Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

MYH2
NM_017534.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.291

Variant links:

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

MYH2 links:

ENSG00000272736 (HGNC:):

ENSG00000272736 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH2. . Gene score misZ 1.9724 (greater than the threshold 3.09). Trascript score misZ 4.733 (greater than threshold 3.09). GenCC has associacion of gene with childhood-onset autosomal recessive myopathy with external ophthalmoplegia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, myopathy, proximal, and ophthalmoplegia.

BP4

Computational evidence support a benign effect (MetaRNN=0.031896353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6 linkuse as main transcript	c.2823G>T	p.Glu941Asp	missense_variant	23/40	ENST00000245503.10	NP_060004.3	Q9UKX2-1
MYH2	NM_001100112.2 linkuse as main transcript	c.2823G>T	p.Glu941Asp	missense_variant	23/40		NP_001093582.1	Q9UKX2-1
MYHAS	NR_125367.1 linkuse as main transcript	n.168-37588C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10 linkuse as main transcript	c.2823G>T	p.Glu941Asp	missense_variant	23/40	1	NM_017534.6	ENSP00000245503.5		Q9UKX2-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.000691

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000442

AC:

111

AN:

251214

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000669

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000761

AC:

1112

AN:

1461530

Hom.:

Cov.:

AF XY:

0.000758

AC XY:

551

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000910

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000493

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000470

Hom.:

Bravo

AF:

0.000654

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000934

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 941 of the MYH2 protein (p.Glu941Asp). This variant is present in population databases (rs138206136, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 465931). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH2 protein function with a negative predictive value of 80%. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.3

L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.22

Sift

Benign

0.12

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.025

B;B

Vest4

0.26

MutPred

0.37

Loss of stability (P = 0.1167);Loss of stability (P = 0.1167);

MVP

0.79

MPC

0.64

ClinPred

0.013

GERP RS

1.9

Varity_R

0.083

gMVP

0.41

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

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