Variant chr2-73901424-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_001615.4(ACTG2):c.113G>A(p.Arg38His) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTG2
NM_001615.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.93

Variant links:

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]

ACTG2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 2-73901424-G-A is Pathogenic according to our data. Variant chr2-73901424-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217521.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-73901424-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4 linkuse as main transcript	c.113G>A	p.Arg38His	missense_variant	2/9	ENST00000345517.8
ACTG2	NM_001199893.2 linkuse as main transcript	c.113G>A	p.Arg38His	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8 linkuse as main transcript	c.113G>A	p.Arg38His	missense_variant	2/9	1	NM_001615.4	P1	P63267-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727166

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D;D;.;D

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;.;T;T;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.9

N;N;D;D;N

REVEL

Pathogenic

0.82

Sift4G

Benign

0.089

T;T;T;T;T

Polyphen

0.17, 1.0

.;B;D;.;B

Vest4

0.87

MutPred

0.86

Loss of methylation at R38 (P = 0.0294);Loss of methylation at R38 (P = 0.0294);Loss of methylation at R38 (P = 0.0294);Loss of methylation at R38 (P = 0.0294);Loss of methylation at R38 (P = 0.0294);

MVP

1.0

MPC

1.6

ClinPred

0.97

GERP RS

3.9

Varity_R

0.80

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over