rs797044959
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5PP2PP3_StrongPP5_Very_Strong
The NM_001615.4(ACTG2):c.770G>A(p.Arg257His) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R257C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ACTG2
NM_001615.4 missense
NM_001615.4 missense
Scores
11
4
1
Clinical Significance
Conservation
PhyloP100: 9.96
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 15 ACMG points.
PM5
?
Other missense variant is known to change same aminoacid residue: 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.
PP2
?
Missense variant where missense usually causes diseases, ACTG2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant 2-73914836-G-A is Pathogenic according to our data. Variant chr2-73914836-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73914836-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTG2 | NM_001615.4 | c.770G>A | p.Arg257His | missense_variant | 7/9 | ENST00000345517.8 | |
ACTG2 | NM_001199893.2 | c.641G>A | p.Arg214His | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTG2 | ENST00000345517.8 | c.770G>A | p.Arg257His | missense_variant | 7/9 | 1 | NM_001615.4 | P1 | |
ACTG2 | ENST00000409624.1 | c.770G>A | p.Arg257His | missense_variant | 8/10 | 2 | P1 | ||
ACTG2 | ENST00000409731.7 | c.641G>A | p.Arg214His | missense_variant | 6/8 | 2 | |||
ACTG2 | ENST00000438902.6 | c.*835G>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/10 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1449758Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 719538
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1449758
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
719538
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Visceral myopathy 1 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Mar 26, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2012 | Co-segregation data for this variant is currently unavailable. This amino acid position is highly conserved in available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.988 (sensitivity: 0.53; specificity: 0.95) - |
Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 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: 26647307, 25998219, 24901346, 26813947, 27481187, 27007401, 31965297) - |
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 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
0.95
.;Loss of catalytic residue at R257 (P = 0.0436);Loss of catalytic residue at R257 (P = 0.0436);
MVP
MPC
2.6
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