rs387907072
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001256545.2(MEGF10):āc.2320T>Cā(p.Cys774Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_001256545.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MEGF10 | NM_001256545.2 | c.2320T>C | p.Cys774Arg | missense_variant | 18/25 | ENST00000503335.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MEGF10 | ENST00000503335.7 | c.2320T>C | p.Cys774Arg | missense_variant | 18/25 | 1 | NM_001256545.2 | P1 | |
MEGF10 | ENST00000274473.6 | c.2320T>C | p.Cys774Arg | missense_variant | 19/26 | 1 | P1 | ||
MEGF10 | ENST00000506709.1 | n.561T>C | non_coding_transcript_exon_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251428Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135880
GnomAD4 exome AF: 0.0000451 AC: 66AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727220
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
MEGF10-related myopathy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 774 of the MEGF10 protein (p.Cys774Arg). This variant is present in population databases (rs387907072, gnomAD 0.005%). This missense change has been observed in individuals with congenital myopathy (PMID: 22101682, 22371254). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MEGF10 function (PMID: 23954233, 28498977). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2022 | Published functional studies suggest a damaging effect with impaired proliferation and migration of myoblasts (Saha et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34740639, 34328698, 23954233, 22101682, 34828389, Chahin_2015_Abstract, 27460346, 27170117, 31267131, 22371254, 28498977) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 18, 2019 | - - |
Congenital myopathy 10b, mild variant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at