chr2-73901429-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001615.4(ACTG2):c.118C>T(p.Arg40Cys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001615.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTG2 | NM_001615.4 | c.118C>T | p.Arg40Cys | missense_variant | 2/9 | ENST00000345517.8 | |
ACTG2 | NM_001199893.2 | c.118C>T | p.Arg40Cys | missense_variant | 2/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTG2 | ENST00000345517.8 | c.118C>T | p.Arg40Cys | missense_variant | 2/9 | 1 | NM_001615.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Visceral myopathy 1 Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | Favorable outcome for genotype-phenotype correlations - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Mar 27, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 22, 2021 | ACMG classification criteria: PS4 supporting, PM2, PM6, PP2, PP3 - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 24, 2015 | The R40C variant in the ACTG2 gene has been reported previously in the apparently de novo, heterozygous state in one individual with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) (Wangler et al., 2014). The R40C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R40C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (R40H) and at nearby residue (M45T), have been reported in the Human Gene Mutation Database in association with MMIHS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R40C as a likely pathogenic variant - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
ACTG2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2023 | The ACTG2 c.118C>T variant is predicted to result in the amino acid substitution p.Arg40Cys. This variant has been reported as de novo and of unknown inheritance in two patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (Wangler et al. 2014. PubMed ID: 24676022; Halim et al. 2015. PubMed ID: 26647307). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at