rs587777388
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001615.4(ACTG2):c.400T>A(p.Tyr134Asn) variant causes a missense change involving the alteration of a 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ACTG2
NM_001615.4 missense
NM_001615.4 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 7.98
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.
PM2
Very rare variant in population databases, with high coverage;
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, 0.987
PP5
Variant 2-73909088-T-A is Pathogenic according to our data. Variant chr2-73909088-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73909088-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTG2 | NM_001615.4 | c.400T>A | p.Tyr134Asn | missense_variant | 5/9 | ENST00000345517.8 | NP_001606.1 | |
ACTG2 | NM_001199893.2 | c.271T>A | p.Tyr91Asn | missense_variant | 4/8 | NP_001186822.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTG2 | ENST00000345517.8 | c.400T>A | p.Tyr134Asn | missense_variant | 5/9 | 1 | NM_001615.4 | ENSP00000295137.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 08, 2022 | The inherited c.400T>A variant has previously been reported as de novo in an individual with prune belly syndrome, MMIHS, and megacystis [PMID:24676022]. The c.400T>A variant is absent in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of US), suggesting it is not a common benign variant in the populations represented in those databases. The c.400T>A variant is located in exon 5 of this 9-exon gene. In silico predictions are in favor of damaging effect for p.(Tyr134Asn) [(CADD v1.6 = 28.6, REVEL = 0.978)]; however, there are no functional studies to support or refute these predictions. The variant is reported in ClinVar [ClinVar ID:132805] as pathogenic in association with Visceral myopathy. Based on available evidence, this inherited c.400T>A, p.Tyr134Asn variant identified in ACTG2 is classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Visceral myopathy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Mar 27, 2014 | - - |
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
Uncertain
D
LIST_S2
Uncertain
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
D;D;D
Polyphen
0.070
.;B;B
Vest4
MutPred
0.91
.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
MPC
2.3
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