chr2-73901434-C-A

Position:

• chr2-73901434-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001615.4(ACTG2):​c.123C>A​(p.His41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.54

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 Uncertain_significance. Variant got 5 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, 3 uncertain in NM_001615.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.123C>A	p.His41Gln	missense_variant	2/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.123C>A	p.His41Gln	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.123C>A	p.His41Gln	missense_variant	2/9	1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Visceral myopathy 1 Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini

Apr 28, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.67	.;D;D;.;D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.3	L;L;.;.;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N;D;D;D;D
REVEL	Pathogenic	0.68
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.0010, 0.99	.;B;D;.;B
Vest4		0.80
MutPred		0.59		Loss of methylation at R38 (P = 0.0525);Loss of methylation at R38 (P = 0.0525);Loss of methylation at R38 (P = 0.0525);Loss of methylation at R38 (P = 0.0525);Loss of methylation at R38 (P = 0.0525);
MVP		1.0
MPC		1.3
ClinPred		0.37	T
GERP RS		0.34
Varity_R		0.80
gMVP		0.84

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: rs774409368; hg19: chr2-74128561;