chr17-10533312-A-G
Variant names:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_017534.6(MYH2):āc.2414T>Cā(p.Val805Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00049 ( 0 hom., cov: 32)
Exomes š: 0.00039 ( 5 hom. )
Consequence
MYH2
NM_017534.6 missense
NM_017534.6 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 1.58
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.011940777).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000487 (74/152052) while in subpopulation EAS AF= 0.0127 (66/5180). AF 95% confidence interval is 0.0103. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 5 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.2414T>C | p.Val805Ala | missense_variant | Exon 21 of 40 | ENST00000245503.10 | NP_060004.3 | |
MYH2 | NM_001100112.2 | c.2414T>C | p.Val805Ala | missense_variant | Exon 21 of 40 | NP_001093582.1 | ||
MYHAS | NR_125367.1 | n.168-34225A>G | intron_variant | Intron 2 of 10 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000487 AC: 74AN: 151934Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000748 AC: 188AN: 251434Hom.: 2 AF XY: 0.000648 AC XY: 88AN XY: 135880
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GnomAD4 exome AF: 0.000388 AC: 567AN: 1461832Hom.: 5 Cov.: 31 AF XY: 0.000355 AC XY: 258AN XY: 727220
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GnomAD4 genome AF: 0.000487 AC: 74AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.000498 AC XY: 37AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Myopathy, proximal, and ophthalmoplegia Pathogenic:1Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Likely pathogenic, flagged submission | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2025 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 11, 2024 | BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2019 | This variant is associated with the following publications: (PMID: 22349865, 27066573) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.1% East Asian ExAC, 2 homozygotes, not in ClinVar. Cai 2011 reported the variant in 3/21 Jpanese patients with inclusion body myositis. Clinical features of IBM include adult-onset weakness of proximal or distal muscle and normal or slightly elevated serum creatine kinase (CK) level. This variant has not been associated with myopathy ith external ophthalmoplegia. Therefore, despite of the classification of the variant, I do not think the disease meets criteria for reporting in BabySeq. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at