rs138206136

Positions:

• chr17-10529949-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The ENST00000245503.10(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E941K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: MYH2 ENST00000245503.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.291

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]

(HGNC:):

ACMG classification

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	c.2823G>T	p.Glu941Asp	missense_variant	23/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-37588C>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.2823G>T	p.Glu941Asp	missense_variant	23/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.2823G>T	p.Glu941Asp	missense_variant	23/40	1	NM_017534.6	ENSP00000245503	P1
	ENST00000399342.6	n.207-3375C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152102 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135792

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.: 0 Cov.: 34 AF XY: 0.000758 AC XY: 551 AN XY: 727036

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: 75 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74414

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.: 0

Bravo AF: 0.000654

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000934 AC: 8

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2019	- -

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	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Pathogenic	0.80	T
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	T
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

Other links and lift over

dbSNP: rs138206136; hg19: chr17-10433266;