chr17-10521356-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_017534.6(MYH2):​c.5750A>G​(p.Asp1917Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1917N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH2
NM_017534.6 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH2NM_017534.6 linkuse as main transcriptc.5750A>G p.Asp1917Gly missense_variant 40/40 ENST00000245503.10
MYHASNR_125367.1 linkuse as main transcriptn.168-46181T>C intron_variant, non_coding_transcript_variant
MYH2NM_001100112.2 linkuse as main transcriptc.5750A>G p.Asp1917Gly missense_variant 40/40

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH2ENST00000245503.10 linkuse as main transcriptc.5750A>G p.Asp1917Gly missense_variant 40/401 NM_017534.6 P1Q9UKX2-1
ENST00000399342.6 linkuse as main transcriptn.207-11968T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1917 of the MYH2 protein (p.Asp1917Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH2 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
.;D;D;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
.;.;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Pathogenic
3.6
.;H;H;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
0.10
N;D;D;.
REVEL
Pathogenic
0.75
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Benign
0.69
T;D;D;T
Polyphen
1.0
.;D;D;.
Vest4
0.80
MutPred
0.60
.;Loss of stability (P = 0.0269);Loss of stability (P = 0.0269);.;
MVP
0.97
MPC
1.3
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.52
gMVP
0.32

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: chr17-10424673; API