rs797044959

Positions:

• chr2-73914836-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.770G>A​(p.Arg257His) 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. R257C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.96

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 chr2-73914835-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, 0.987
• PP5: Variant 2-73914836-G-A is Pathogenic according to our data. Variant chr2-73914836-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73914836-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.770G>A	p.Arg257His	missense_variant	7/9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.641G>A	p.Arg214His	missense_variant	6/8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.770G>A	p.Arg257His	missense_variant	7/9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449758 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 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, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 26, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2012

Co-segregation data for this variant is currently unavailable. This amino acid position is highly conserved in available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.988 (sensitivity: 0.53; specificity: 0.95) -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2022

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, 25998219, 24901346, 26813947, 27481187, 27007401, 31965297) -

Chronic intestinal pseudoobstruction;C1855311:Megacystis Pathogenic:1

Pathogenic, no assertion criteria provided

research

UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini

May 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.99
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91
MutPred		0.95		.;Loss of catalytic residue at R257 (P = 0.0436);Loss of catalytic residue at R257 (P = 0.0436);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044959; hg19: chr2-74141963;