chr2-73901430-G-A

Position:

• 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:12 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, 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 chr2-73901429-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 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, 0.95
• 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:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Aug 01, 2016	- -
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	- -
not provided, no classification provided	literature only	GeneReviews	-	Favorable outcome for genotype-phenotype correlations -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Arg40His variant leads to a substitution of the arginine at amino acid position 40 with a histidine. This is a recurrent variant that has been reported in multiple unrelated individuals with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) or chronic intestinal pseudo-obstruction with megacystis (CIPO-M) (PMID: 26072522, PMID: 31769566, PMID: 31216405, PMID: 33294969, PMID: 34958143, PMID: 24676022). The p.Arg40His is absent from large population studies (gnomAD v2.1.1). In silico tools predict the p.Arg40His variant to be damaging. Another variant at the same amino acid position (p.Arg40Cys) has been reported in multiple affected individuals (PMID: 34958143, PMID: 24676022, PMID: 26647307). Individuals with the p.Arg40His and p.Arg40Cys variants have been found to have a less severe clinical presentation and more favorable outcome in comparison to those with other ACTG2 pathogenic variants (PMID: 26072522, PMID: 31769566). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 16, 2023	The c.119G>A variant in ACTG2 has previously been reported in multiple affected individuals with ACTG2-related visceral myopathy, Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and intestinal pseudo-obstruction [PMID: 24676022, 28422808, 29781137, 33294969, 26647307] and found be segregated with disease in affected family members [PMID: 24676022]. The c.119G>A variant has been deposited in ClinVar [ClinVar ID: 132802] as Pathogenic/Likely Pathogenic and the variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.119G>A variant in ACTG2 is located in exon 2 of this 9-exon gene and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 40 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg40His) [(CADD v1.6 =25.7, REVEL =0.943)]; however, there are no functional studies to support or refute these predictions. Another missense substitution p.(Arg40Cys) affecting the same protein residue have been reported in the literature [PMID: 24676022, 26647307, 29781137] and ClinVar [ClinVar ID: 132799] in individuals with ACTG2 related disorders. Additionally p.Arg40 has been reported as one of the recurrent arginine substitutions in the ACTG2 and reported to be associated with mixed phenotypic severity and favorable clinical outcome in 6/8 examined individuals [PMID: 31769566]. Based on available evidence this inherited c.119G>A, p.(Arg40His) heterozygous variant identified in ACTG2 is classified Pathogenic. -

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

- -

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
DEOGEN2	Uncertain	0.77	.;D;D;.;D
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;