rs864309492

chr2-73913626-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.593G>A(p.Gly198Asp) 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. 12/21 in silico tools predict a damaging 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. G198V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr2-73913626-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803217.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACTG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 2-73913626-G-A is Pathogenic according to our data. Variant chr2-73913626-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73913626-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.593G>A	p.Gly198Asp	missense_variant	6/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.464G>A	p.Gly155Asp	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.593G>A	p.Gly198Asp	missense_variant	6/9	1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:2

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	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Feb 17, 2017	The c.593G>A (p.Gly198Asp) variant is a missense variant in the ACTG2 gene. This variant has a previously reported in a patient with megacystis-microcolon-intestinal hypoperistalsis syndrome (PMID: 24676022). This variant is not seen in ExAC database thus it is presumed to be rare. This variant is predicted to be damaging based on in silico modeling. No functional studies exist for this particular variant. Based on the combined evidence and the variant being de novo in this patient, the variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.99
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.69	.;P;P
Vest4		0.94
MutPred		0.86		.;Gain of phosphorylation at T195 (P = 0.121);Gain of phosphorylation at T195 (P = 0.121);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.94

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: rs864309492; hg19: chr2-74140753;