rs12600539

Positions:

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

Variant summary

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

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:):

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.324A>T	p.Glu108Asp	missense_variant	4/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-20038T>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.324A>T	p.Glu108Asp	missense_variant	4/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.324A>T	p.Glu108Asp	missense_variant	4/40	1	NM_017534.6	ENSP00000245503	P1

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;.;.
MutationTaster	Benign	0.00018	P;P;P
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;