rs78001248

Positions:

• chr2-73913565-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001615.4(ACTG2):​c.532C>T​(p.Arg178Cys) 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. 12/21 in silico tools predict a damaging 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. R178H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

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 chr2-73913566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 132801.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, 0.966
• PP5: Variant 2-73913565-C-T is Pathogenic according to our data. Variant chr2-73913565-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 132800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73913565-C-T is described in Lovd as [Pathogenic]. Variant chr2-73913565-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.532C>T	p.Arg178Cys	missense_variant	6/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.403C>T	p.Arg135Cys	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.532C>T	p.Arg178Cys	missense_variant	6/9	1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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, no assertion criteria provided	research	UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini	May 02, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Published functional studies demonstrate a lack of mutant protein co-localization with actin filaments and decreased collagen contraction capacity (Halim et al., 2016; Thorson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26813947, 26647307, 24337657, 24676022, 27481187, 32621347, 34980693) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Arg178Cys variant (c.532C>T, exon 6) is a recurrent variant that has previously been reported in multiple individuals with MMIHS (PMID: 26647307, PMID: 24337657, PMID: 24676022, PMID: 27481187). The p.Arg178Cys variant is absent from large population cohorts (gnomAD v2.1.1). Further supporting pathogenicity, other missense changes at this same residue (p.Arg178His, p.Arg178Leu, p.Arg178Ser) have also been reported as de novo changes in patients with sporadic MMIHS (PMID: 26647307, PMID: 24337657, PMID: 27481187, PMID: 25998219, PMID: 29608093). -

ACTG2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2024

The ACTG2 c.532C>T variant is predicted to result in the amino acid substitution p.Arg178Cys. This variant was reported in individuals with megacystis-microcolon-intestinal hypoperistalsis syndrome, including multiple de novo cases (Thorson et al. 2014. PubMed ID: 24337657; Wangler et al. 2014. PubMed ID: 24676022; Halim et al. 2015. PubMed ID: 26647307; Moreno et al. 2016. PubMed ID: 27481187). Functional studies showed that this variant impaired polymerization and reduced cell contractility (Halim et al. 2016. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.98
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.12	.;B;B
Vest4		0.86
MutPred		0.81		.;Gain of catalytic residue at L179 (P = 0.0093);Gain of catalytic residue at L179 (P = 0.0093);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs78001248; hg19: chr2-74140692; COSMIC: COSV100609536; COSMIC: COSV100609536;