chr2-73909130-C-A

Position:

• chr2-73909130-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001615.4(ACTG2):​c.442C>A​(p.Arg148Ser) variant causes a missense change. 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. R148L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.03

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73909131-G-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, 0.962
• PP5: Variant 2-73909130-C-A is Pathogenic according to our data. Variant chr2-73909130-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 132797.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-73909130-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG2	NM_001615.4	c.442C>A	p.Arg148Ser	missense_variant	5/9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.313C>A	p.Arg105Ser	missense_variant	4/8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.442C>A	p.Arg148Ser	missense_variant	5/9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Visceral myopathy 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 22, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative has been suggested as a mechanism of disease in this gene and is associated with visceral myopathy 1 (MIM#155310), a phenotype which encompasses megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS; MIM#619431) and chronic intestinal pseudoobstruction (CIPO) (PMIDs: 26072522, 26647307, 32814715). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial clinical variability has been reported (OMIM, PMID: 26072522). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three unrelated individuals with ACTG2-related features, including one family with multiple affected members with familial visceral myopathy (PMIDs: 22960657, 26813947, 24777424). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been identified in a three-generation family with visceral myopathy and is observed to segregate with the familial visceral myopathy phenotype (PMID: 22960657). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Sarcoma cells transfected with the R148S variant show interference with endogenous actin cytoskeletal organisation and cell contractility (PMID: 22960657). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2014	- -

Chronic intestinal pseudoobstruction 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	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.83	.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.95
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.98	.;D;D
Vest4		0.93
MutPred		0.81		.;Loss of methylation at R148 (P = 0.0112);Loss of methylation at R148 (P = 0.0112);
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.99

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: rs587777383; hg19: chr2-74136257;