17-10539263-T-C

Position:

• chr17-10539263-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_017534.6(MYH2):​c.1358A>G​(p.Lys453Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

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]

MYHAS (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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=0.32107586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.1358A>G	p.Lys453Arg	missense_variant	14/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-28274T>C		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.1358A>G	p.Lys453Arg	missense_variant	14/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.1358A>G	p.Lys453Arg	missense_variant	14/40	1	NM_017534.6	ENSP00000245503	P1
MYH2	ENST00000532183.6	c.1358A>G	p.Lys453Arg	missense_variant	13/17	1		ENSP00000433944
MYH2	ENST00000622564.4	c.1358A>G	p.Lys453Arg	missense_variant	14/18	1		ENSP00000482463
MYH2	ENST00000397183.6	c.1358A>G	p.Lys453Arg	missense_variant	14/40	5		ENSP00000380367	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 07, 2017

This sequence change replaces lysine with arginine at codon 453 of the MYH2 protein (p.Lys453Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;N;N;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.021	D;D;D;.
Sift4G	Benign	0.069	T;T;T;T
Polyphen		0.99	.;D;D;.
Vest4		0.13
MutPred		0.67		Loss of methylation at K453 (P = 0.0076);Loss of methylation at K453 (P = 0.0076);Loss of methylation at K453 (P = 0.0076);Loss of methylation at K453 (P = 0.0076);
MVP		0.78
MPC		0.64
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.54

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: rs1555571482; hg19: chr17-10442580;