2-73913566-G-A

Position:

• chr2-73913566-G-A

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>A​(p.Arg178His) 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 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:6 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 Lovd as [Pathogenic].
• 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, 0.94
• PP5: Variant 2-73913566-G-A is Pathogenic according to our data. 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. Variant chr2-73913566-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG2	NM_001615.4	c.533G>A	p.Arg178His	missense_variant	6/9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.404G>A	p.Arg135His	missense_variant	5/8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.533G>A	p.Arg178His	missense_variant	6/9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:3 Other:1

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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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

Aug 09, 2013

The c.533G>A (p.R178H) alteration is located in coding exon 5 of the ACTG2 gene. This alteration results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties.The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the ACTG2 c.533G>A (p.R178H) alteration was not observed among 6,502 individuals tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is highly conserved throughout evolution:The R178 amino acid is conserved throughout vertebrates as well as among all the six actin proteins in human.The alteration is predicted benign by in silico models:The p.R178H alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses.The alteration is de novo in the proband herein:Co-segregation analysis of the c.533G>A (p.R178H alteration in this family revealed that the unaffected mother and father do not carry this alteration, indicating a likely de novo mutation occurrence.Based on the available evidence, the ACTG2 c.533G>A (p.R178H) alteration is classified as a pathogenic mutation. -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2022

Published functional studies demonstrate a damaging effect on actin polymerization (Halim D et al., 2016); 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, 24676022, 32621347, 33859849, 25998219, 34071279, 32810037, 34980693) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.96
Sift4G	Benign	0.082	T;T;T
Polyphen		0.052	.;B;B
Vest4		0.78
MutPred		0.83		.;Gain of catalytic residue at M177 (P = 0.0249);Gain of catalytic residue at M177 (P = 0.0249);
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.92

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; COSMIC: COSV61827671; COSMIC: COSV61827671;