2-73913566-G-T

Position:

• chr2-73913566-G-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.533G>T​(p.Arg178Leu) 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. R178C) 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:4 O:1
• Conservation: PhyloP100: 10.0

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 chr2-73913565-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.
• PP2: Missense variant where missense usually causes diseases, ACTG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 2-73913566-G-T is Pathogenic according to our data. Variant chr2-73913566-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 132798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73913566-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.533G>T	p.Arg178Leu	missense_variant	6/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.404G>T	p.Arg135Leu	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.533G>T	p.Arg178Leu	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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon -
Pathogenic, no assertion criteria provided	research	UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini	May 02, 2015	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2023

The c.533G>T (p.R178L) alteration is located in exon 6 (coding exon 5) of the ACTG2 gene. This alteration results from a G to T substitution at nucleotide position 533, causing the arginine (R) at amino acid position 178 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The de novo c.533G>T (p.R178L) alteration has been previously identified via whole exome sequencing in a female patient who was diagnosed after birth with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) (Thorson, 2014). An additional patient was recently reported with a de novo p.R178L alteration who was diagnosed prenatally with megabladder and subsequently with MMIHS after birth (Halim, 2016). This patient died at 8 months of age from multiple organ failure. De novo alterations in the same amino acid (p.R178C and p.R178H) have also been reported in patients with MMIHS (Thorson, 2014; Wangler, 2014). This amino acid position is highly conserved in available vertebrate species. Structural modeling demonstrates that the p.R178 amino acid is located within the hinge separating domains III and IV and interacts with amino acid residue p.H74 to lock ACTG2 into a conformation allowing for polymerization into thin filaments (Otterbein, 2001; Thorson, 2014). The p.R178L substitution is predicted to destabilize the interaction between p.R178 and p.H74, resulting in depolymerization of thin filaments into monomeric actin (Thorson, 2014). Functional analysis demonstrated that the p.R178L alteration leads to impaired ACTG2 polymerization and reduced cell contractility (Halim, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2022

Published functional studies demonstrate a damaging effect, showing impaired polymerization with actin as well as reduced cellular contractility (Halim et al., 2016; Thorson et al., 2014); 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, 27481187, 24337657) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.62	T;.;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.99
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.72	.;P;P
Vest4		0.87
MutPred		0.80		.;Loss of methylation at R178 (P = 0.0384);Loss of methylation at R178 (P = 0.0384);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
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: rs587777384; hg19: chr2-74140693;