NM_001615.4:c.119G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001615.4(ACTG2):c.119G>A(p.Arg40His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

ACTG2
NM_001615.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 9.53

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 Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-73901429-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the ACTG2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.3487 (above the threshold of 3.09). Trascript score misZ: 4.3482 (above the threshold of 3.09). GenCC associations: The gene is linked to visceral myopathy 1, familial visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 2-73901430-G-A is Pathogenic according to our data. Variant chr2-73901430-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73901430-G-A is described in Lovd as [Pathogenic]. Variant chr2-73901430-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG2	NM_001615.4 link	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 9	ENST00000345517.8	NP_001606.1	P63267-1
ACTG2	NM_001199893.2 link	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 8		NP_001186822.1	P63267-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8 link	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 9	1	NM_001615.4	ENSP00000295137.3		P63267-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Visceral myopathy 1

Pathogenic:5Other:1

Mar 27, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;research

- -

Mar 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Favorable outcome for genotype-phenotype correlations -

Oct 12, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg40His variant leads to a substitution of the arginine at amino acid position 40 with a histidine. This is a recurrent variant that has been reported in multiple unrelated individuals with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) or chronic intestinal pseudo-obstruction with megacystis (CIPO-M) (PMID: 26072522, PMID: 31769566, PMID: 31216405, PMID: 33294969, PMID: 34958143, PMID: 24676022). The p.Arg40His is absent from large population studies (gnomAD v2.1.1). In silico tools predict the p.Arg40His variant to be damaging. Another variant at the same amino acid position (p.Arg40Cys) has been reported in multiple affected individuals (PMID: 34958143, PMID: 24676022, PMID: 26647307). Individuals with the p.Arg40His and p.Arg40Cys variants have been found to have a less severe clinical presentation and more favorable outcome in comparison to those with other ACTG2 pathogenic variants (PMID: 26072522, PMID: 31769566). -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5

Pathogenic:2

Mar 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 16, 2023

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>A variant in ACTG2 has previously been reported in multiple affected individuals with ACTG2-related visceral myopathy, Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and intestinal pseudo-obstruction [PMID: 24676022, 28422808, 29781137, 33294969, 26647307] and found be segregated with disease in affected family members [PMID: 24676022]. The c.119G>A variant has been deposited in ClinVar [ClinVar ID: 132802] as Pathogenic/Likely Pathogenic and the variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.119G>A variant in ACTG2 is located in exon 2 of this 9-exon gene and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 40 of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg40His) [(CADD v1.6 =25.7, REVEL =0.943)]; however, there are no functional studies to support or refute these predictions. Another missense substitution p.(Arg40Cys) affecting the same protein residue have been reported in the literature [PMID: 24676022, 26647307, 29781137] and ClinVar [ClinVar ID: 132799] in individuals with ACTG2 related disorders. Additionally p.Arg40 has been reported as one of the recurrent arginine substitutions in the ACTG2 and reported to be associated with mixed phenotypic severity and favorable clinical outcome in 6/8 examined individuals [PMID: 31769566]. Based on available evidence this inherited c.119G>A, p.(Arg40His) heterozygous variant identified in ACTG2 is classified Pathogenic. -

not provided

Pathogenic:2

Jun 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34958143, 31216405, 31769566, 33294969, 36509086, 35695198, 29781137, 28422808, 24676022) -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTG2: PS2:Very Strong, PM2, PP2, PP3 -

Visceral neuropathy, familial, 3, autosomal dominant

Pathogenic:1

Jun 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Visceral myopathy 1;C5543636:Megacystis-microcolon-intestinal hypoperistalsis syndrome 5

Pathogenic:1

Dec 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Constipation

Pathogenic:1

Sep 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3 (PMID 26647307), PS4, PM2, PM5, PP3 -

Chronic intestinal pseudoobstruction

Pathogenic:1

May 25, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;D;D;.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;.;D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;.;.;M

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.1

N;N;D;D;N

REVEL

Pathogenic

0.94

Sift4G

Uncertain

0.028

D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;.;D

Vest4

0.67

MutPred

0.83

Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);Gain of methylation at R38 (P = 0.0737);

MVP

1.0

MPC

2.4

ClinPred

0.99

GERP RS

3.9

Varity_R

0.82

gMVP

0.75

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

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