rs587777387

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001615.4(ACTG2):c.769C>T(p.Arg257Cys) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTG2
NM_001615.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 4.10

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

visceral myopathy 1
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial visceral myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
megacystis-microcolon-intestinal hypoperistalsis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 chr2-73914836-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, megacystis-microcolon-intestinal hypoperistalsis syndrome, familial visceral myopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 2-73914835-C-T is Pathogenic according to our data. Variant chr2-73914835-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 132803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG2	NM_001615.4 link	c.769C>T	p.Arg257Cys	missense_variant	Exon 7 of 9	ENST00000345517.8	NP_001606.1	P63267-1
ACTG2	NM_001199893.2 link	c.640C>T	p.Arg214Cys	missense_variant	Exon 6 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.769C>T	p.Arg257Cys	missense_variant	Exon 7 of 9	1	NM_001615.4	ENSP00000295137.3		P63267-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720108

African (AFR)

AF:

0.00

AC:

AN:

33174

American (AMR)

AF:

0.00

AC:

AN:

44018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

85204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104314

Other (OTH)

AF:

0.00

AC:

AN:

59854

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000499

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Visceral myopathy 1

Pathogenic:9Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon -

Mar 27, 2014

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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.Arg257Cys variant results in substitution of arginine at codon 257 with cysteine within exon 7. This is a recurrent variant that has previously been reported in multiple unrelated individuals with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) or chronic intestinal pseudo-obstruction with megacystis (CIPO-M) (PMID: 25998219 and others). This variant is absent from large population studies (gnomAD v4.1.0). -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative has been suggested as a mechanism of disease in this gene and is associated with visceral myopathy 1 (MIM#155310), a phenotype which encompasses megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS; MIM#619431) and chronic intestinal pseudoobstruction (CIPO) (PMID: 26072522, 26647307, 32814715). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial clinical variability has been reported (OMIM, PMID: 26072522). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as de novo in several individuals with CIPO (PMID: 29781137). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 14, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.769C>T;p.(Arg257Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 132803; OMIM: 102545.0007; PMID: 33294969; 26072522; 31769566) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Actin) - PM1. This variant is not present in population databases (rs587777387, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 208792 - c.770G>A;p.(Arg257His)) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 33294969; 31769566) - PM6_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Arg257Cys variant was identified by our study in one individual with Visceral Myopathy. Trio analysis showed this variant to be de novo. The p.Arg257Cys variant is pathogenic based off of multiple reports in ClinVar and the literature. -

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 02, 2021

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 33294969, 24676022, 31769566,28422808 PS2, PS4). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg257His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000208792.10, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:5

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 15, 2022

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: 24676022, 25998219, 27007401, 26813947, 29781137, 28422808, 31441039, 30577886, 33294969, 30712878) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Pathogenic:2

Suma Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS4+PM6_VeryStrong+PM5+PP4 -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5

Pathogenic:2

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

- -

Inborn genetic diseases

Pathogenic:1

Mar 27, 2014

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chronic intestinal pseudoobstruction;C1855311:Megacystis

Pathogenic:1

May 02, 2015

UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

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

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

.;H;H

PhyloP100

4.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Pathogenic

0.97

Sift4G

Uncertain

0.017

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.95

MutPred

0.93

.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

4.7

Varity_R

0.91

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over