2-73902698-C-G

Position:

• chr2-73902698-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PS1 PM2 BP4_Moderate

The ENST00000409918.5(ACTG2):​c.330C>G​(p.Phe110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTG2 ENST00000409918.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.79

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 4 ACMG points.

• PS1: Transcript ENST00000409918.5 (ACTG2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 218311
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14938846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.255+210C>G		intron_variant		ENST00000345517.8
ACTG2	NM_001199893.2	c.126+1261C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.255+210C>G		intron_variant		1	NM_001615.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 32

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

case-control

Wangler Lab, Baylor College of Medicine

Sep 30, 2019

Our group reported this variant in the original Wangler et al. 2014 study in a family with two affected individuals and the father's sample was not available. We have since identified this exact variant in a family that is solved by a known pathogenic missense de novo in ACTG2. This along with the fact that all the other known pathogenic variants in ACTG2 are missense alleles occuring in the canonical transcript point to this being a potentially benign variant. However, it cannot be ruled out as a modifier. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	1.5	N
REVEL	Benign	0.24
Sift4G	Uncertain	0.0080	D
Polyphen		0.0	B
Vest4		0.26
MutPred		0.63		Gain of disorder (P = 0.1272);
MVP		0.40
ClinPred		0.053	T
GERP RS		2.4

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: rs768290597; hg19: chr2-74129825;