chr17-10537338-C-T

Position:

• chr17-10537338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017534.6(MYH2):​c.1792G>A​(p.Glu598Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 5.03

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]

ENSG00000272736 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.1792G>A	p.Glu598Lys	missense_variant	16/40	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.1792G>A	p.Glu598Lys	missense_variant	16/40		NP_001093582.1
MYHAS	NR_125367.1	n.168-30199C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.1792G>A	p.Glu598Lys	missense_variant	16/40	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 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	Apr 09, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 499533). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 598 of the MYH2 protein (p.Glu598Lys). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 01, 2019	- -

MYH2-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2024

The MYH2 c.1792G>A variant is predicted to result in the amino acid substitution p.Glu598Lys. This variant was found in multiple members of a family that underwent testing for inclusion body myositis; the family was previously the subject of study demonstrating an autosomal dominant mode of inheritance for inclusion body myositis (internal data; Neville et al. 1992. PubMed ID: 1314344). This variant was also shown to segregate in another family with a chronic inflammatory myopathy and suggestive inclusion body myositis (pedigree LGMD2377 in an unpublished dissertation; https://hdl.handle.net/10161/7169). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;.;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;N;N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D;D;D;.
Sift4G	Uncertain	0.046	D;T;T;D
Polyphen		0.0050	.;B;B;.
Vest4		0.27
MutPred		0.54		Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);Gain of methylation at E598 (P = 0.0044);
MVP		0.83
MPC		0.86
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.60

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: rs1555571267; hg19: chr17-10440655;