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

Genomes: not found (cov: 34)

Consequence

ACTG2
NM_001615.4 missense

Scores

12
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 2.93
Variant links:
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 19 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001615.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-73901430-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 0.962
PP5
Variant 2-73901429-C-T is Pathogenic according to our data. Variant chr2-73901429-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73901429-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTG2NM_001615.4 linkuse as main transcriptc.118C>T p.Arg40Cys missense_variant 2/9 ENST00000345517.8
ACTG2NM_001199893.2 linkuse as main transcriptc.118C>T p.Arg40Cys missense_variant 2/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTG2ENST00000345517.8 linkuse as main transcriptc.118C>T p.Arg40Cys missense_variant 2/91 NM_001615.4 P1P63267-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Visceral myopathy 1 Pathogenic:2Other:1
not provided, no classification providedliterature onlyGeneReviews-Favorable outcome for genotype-phenotype correlations -
Pathogenic, criteria provided, single submitterresearchLupski Lab, Baylor-Hopkins CMG, Baylor College of MedicineMar 27, 2014- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinApr 22, 2021ACMG classification criteria: PS4 supporting, PM2, PM6, PP2, PP3 -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxNov 24, 2015The 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2019- -
ACTG2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 16, 2023The 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 providedliterature onlyOMIMMar 01, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
.;D;D;.;D
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D;.;D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;.;.;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.0
D;D;D;D;D
REVEL
Pathogenic
0.96
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
.;D;D;.;D
Vest4
0.73
MutPred
0.84
Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
3.0
Varity_R
0.91
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777385; hg19: chr2-74128556; API