17-10537745-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_017534.6(MYH2):c.1507G>A(p.Glu503Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E503Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.1507G>A	p.Glu503Lys	missense_variant	15/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-29792C>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.1507G>A	p.Glu503Lys	missense_variant	15/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.1507G>A	p.Glu503Lys	missense_variant	15/40	1	NM_017534.6	P1
	ENST00000399342.6	n.466C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.6	H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.97	.;D;D;.
Vest4		0.88
MutPred		0.89		Gain of methylation at E503 (P = 0.0276);Gain of methylation at E503 (P = 0.0276);Gain of methylation at E503 (P = 0.0276);Gain of methylation at E503 (P = 0.0276);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.99

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: rs865974946; hg19: chr17-10441062;