2-73901378-G-A

Position:

• chr2-73901378-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001615.4(ACTG2):​c.67G>A​(p.Ala23Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

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.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.67G>A	p.Ala23Thr	missense_variant	2/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.67G>A	p.Ala23Thr	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.67G>A	p.Ala23Thr	missense_variant	2/9	1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Visceral myopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;D;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;N;D;N;N
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.027	D;D;D;D;D
Polyphen		0.099, 1.0	.;B;D;.;B
Vest4		0.93
MutPred		0.69		Gain of phosphorylation at A23 (P = 0.0449);Gain of phosphorylation at A23 (P = 0.0449);Gain of phosphorylation at A23 (P = 0.0449);Gain of phosphorylation at A23 (P = 0.0449);Gain of phosphorylation at A23 (P = 0.0449);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.76
gMVP		0.93

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: rs1553394796; hg19: chr2-74128505; COSMIC: COSV61830035;