rs587777386

chr2-73901430-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001615.4(ACTG2):c.119G>A(p.Arg40His) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 9.53

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 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, 3 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 chr2-73901429-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.
• PP2: Missense variant where missense usually causes diseases, ACTG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 2-73901430-G-A is Pathogenic according to our data. 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. Variant chr2-73901430-G-A is described in Lovd as [Pathogenic]. Variant chr2-73901430-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.119G>A	p.Arg40His	missense_variant	2/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.119G>A	p.Arg40His	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.119G>A	p.Arg40His	missense_variant	2/9	1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	Favorable outcome for genotype-phenotype correlations -
Pathogenic, criteria provided, single submitter	clinical testing;research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Mar 27, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Aug 01, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	ACTG2: PS2:Very Strong, PM2, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2023	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: 34958143, 31216405, 31769566, 33294969, 36509086, 35695198, 29781137, 28422808, 24676022) -

Visceral neuropathy, familial, 3, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Visceral myopathy 1;C5543636:Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2014

- -

Chronic intestinal pseudoobstruction Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N;N;D;D;N
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D
Vest4		0.67
MutPred		0.83		Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);
MVP		1.0
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.82
gMVP		0.75

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: rs587777386; hg19: chr2-74128557; COSMIC: COSV100609175;