rs12600539

Variant names:

• chr17-10547499-T-A
• rs12600539
• NM_017534.6:c.324A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10547499-T-A
• chr17-10547499-T-C
• chr17-10547499-T-G

Variant summary

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

The NM_017534.6(MYH2):​c.324A>T​(p.Glu108Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E108E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.39

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: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.324A>T	p.Glu108Asp	missense_variant	Exon 4 of 40	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.324A>T	p.Glu108Asp	missense_variant	Exon 4 of 40		NP_001093582.1
MYHAS	NR_125367.1	n.168-20038T>A		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.324A>T	p.Glu108Asp	missense_variant	Exon 4 of 40	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.38	.;T;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	.;.;T;T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.0	L;L;L;L;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N;N;N;.;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.11	T;T;T;.;.;T
Sift4G	Benign	0.49	T;T;T;T;T;.
Polyphen		0.0	.;B;B;.;.;.
Vest4		0.55
MutPred		0.37		Loss of ubiquitination at K107 (P = 0.1179);Loss of ubiquitination at K107 (P = 0.1179);Loss of ubiquitination at K107 (P = 0.1179);Loss of ubiquitination at K107 (P = 0.1179);.;Loss of ubiquitination at K107 (P = 0.1179);
MVP		0.88
MPC		0.64
ClinPred		0.55	D
GERP RS		6.0
Varity_R		0.14
gMVP		0.55

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: rs12600539; hg19: chr17-10450816;