2-73914835-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001615.4(ACTG2):c.769C>T(p.Arg257Cys) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ACTG2
NM_001615.4 missense
NM_001615.4 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 4.10
Genes affected
ACTG2 (HGNC:145): (actin gamma 2, smooth muscle) Actins are highly conserved proteins that are involved in various types of cell motility and in the maintenance of the cytoskeleton. Three types of actins, alpha, beta and gamma, have been identified in vertebrates. Alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. This gene encodes actin gamma 2; a smooth muscle actin found in enteric tissues. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Based on similarity to peptide cleavage of related actins, the mature protein of this gene is formed by removal of two N-terminal peptides.[provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-73914836-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTG2. . Gene score misZ 3.3487 (greater than the threshold 3.09). Trascript score misZ 4.3482 (greater than threshold 3.09). GenCC has associacion of gene with visceral myopathy 1, familial visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 2-73914835-C-T is Pathogenic according to our data. Variant chr2-73914835-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 132803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73914835-C-T is described in Lovd as [Pathogenic]. Variant chr2-73914835-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTG2 | NM_001615.4 | c.769C>T | p.Arg257Cys | missense_variant | 7/9 | ENST00000345517.8 | NP_001606.1 | |
ACTG2 | NM_001199893.2 | c.640C>T | p.Arg214Cys | missense_variant | 6/8 | NP_001186822.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTG2 | ENST00000345517.8 | c.769C>T | p.Arg257Cys | missense_variant | 7/9 | 1 | NM_001615.4 | ENSP00000295137 | P1 | |
ACTG2 | ENST00000409624.1 | c.769C>T | p.Arg257Cys | missense_variant | 8/10 | 2 | ENSP00000386857 | P1 | ||
ACTG2 | ENST00000409731.7 | c.640C>T | p.Arg214Cys | missense_variant | 6/8 | 2 | ENSP00000386929 | |||
ACTG2 | ENST00000438902.6 | c.*834C>T | 3_prime_UTR_variant, NMD_transcript_variant | 8/10 | 5 | ENSP00000410706 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1450726Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 720108
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1450726
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31
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0
AN XY:
720108
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Visceral myopathy 1 Pathogenic:9Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | The p.Arg257Cys variant results in substitution of arginine at codon 257 with cysteine within exon 7. This is a recurrent variant that has previously been reported in multiple unrelated individuals with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) or chronic intestinal pseudo-obstruction with megacystis (CIPO-M) (PMID: 25998219 and others). This variant is absent from large population studies (gnomAD v4.1.0). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Arg257Cys variant was identified by our study in one individual with Visceral Myopathy. Trio analysis showed this variant to be de novo. The p.Arg257Cys variant is pathogenic based off of multiple reports in ClinVar and the literature. - |
not provided, no classification provided | literature only | GeneReviews | - | High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Mar 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative has been suggested as a mechanism of disease in this gene and is associated with visceral myopathy 1 (MIM#155310), a phenotype which encompasses megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS; MIM#619431) and chronic intestinal pseudoobstruction (CIPO) (PMID: 26072522, 26647307, 32814715). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial clinical variability has been reported (OMIM, PMID: 26072522). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as de novo in several individuals with CIPO (PMID: 29781137). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.769C>T;p.(Arg257Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 132803; OMIM: 102545.0007; PMID: 33294969; 26072522; 31769566) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Actin) - PM1. This variant is not present in population databases (rs587777387, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 208792 - c.770G>A;p.(Arg257His)) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 33294969; 31769566) - PM6_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 33294969, 24676022, 31769566,28422808 PS2, PS4). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg257His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000208792.10, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | 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: 24676022, 25998219, 27007401, 26813947, 29781137, 28422808, 31441039, 30577886, 33294969, 30712878) - |
Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | - - |
Visceral neuropathy, familial, 3, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
Visceral myopathy 1;C5543636:Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics, Suma Genomics | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2014 | - - |
Chronic intestinal pseudoobstruction;C1855311:Megacystis Pathogenic:1
Pathogenic, no assertion criteria provided | research | UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini | May 02, 2015 | - - |
Chronic intestinal pseudoobstruction Pathogenic:1
Pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | May 25, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
0.93
.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at