17-10523116-A-G

Variant names:

• chr17-10523116-A-G
• NM_017534.6:c.5647T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017534.6(MYH2):​c.5647T>C​(p.Ser1883Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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:):

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.5647T>C	p.Ser1883Pro	missense_variant	Exon 39 of 40	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.5647T>C	p.Ser1883Pro	missense_variant	Exon 39 of 40		NP_001093582.1
MYHAS	NR_125367.1	n.168-44421A>G		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.5647T>C	p.Ser1883Pro	missense_variant	Exon 39 of 40	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1

Aug 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 1883 of the MYH2 protein (p.Ser1883Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.072	T;T
Polyphen		0.043	B;B
Vest4		0.54
MutPred		0.56		Loss of phosphorylation at S1883 (P = 0.0197);Loss of phosphorylation at S1883 (P = 0.0197);
MVP		0.90
MPC		0.43
ClinPred		0.86	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-10426433;