rs200217946
Variant names:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2
The NM_017534.6(MYH2):c.3128C>T(p.Ser1043Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,028 control chromosomes in the GnomAD database, including 3 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: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00035 ( 3 hom. )
Consequence
MYH2
NM_017534.6 missense
NM_017534.6 missense
Scores
11
5
3
Clinical Significance
Conservation
PhyloP100: 7.72
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 -10 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.09905121).
BP6
Variant 17-10529471-G-A is Benign according to our data. Variant chr17-10529471-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321678.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000263 (40/152142) while in subpopulation AMR AF= 0.000917 (14/15272). AF 95% confidence interval is 0.000554. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.3128C>T | p.Ser1043Phe | missense_variant | Exon 25 of 40 | ENST00000245503.10 | NP_060004.3 | |
MYH2 | NM_001100112.2 | c.3128C>T | p.Ser1043Phe | missense_variant | Exon 25 of 40 | NP_001093582.1 | ||
MYHAS | NR_125367.1 | n.168-38066G>A | intron_variant | Intron 2 of 10 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000625 AC: 157AN: 251352Hom.: 1 AF XY: 0.000596 AC XY: 81AN XY: 135848
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GnomAD4 exome AF: 0.000350 AC: 512AN: 1461886Hom.: 3 Cov.: 34 AF XY: 0.000348 AC XY: 253AN XY: 727242
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GnomAD4 genome AF: 0.000263 AC: 40AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 12, 2024 | Variant summary: MYH2 c.3128C>T (p.Ser1043Phe) results in a non-conservative amino acid change located in the Myosin Tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251352 control chromosomes in the gnomAD database, including 1 homozygotes. To our knowledge, no occurrence of c.3128C>T in individuals affected with Myopathy, Proximal, And Ophthalmoplegia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 321678). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inclusion Body Myopathy, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Myopathy, proximal, and ophthalmoplegia Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
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