rs587777387

chr2-73914835-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001615.4(ACTG2):c.769C>T(p.Arg257Cys) variant causes a missense change. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 4.10

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 Pathogenic. Variant got 15 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73914836-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ACTG2
• 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 id is 132803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73914835-C-T is described in Lovd as [Pathogenic]. Variant chr2-73914835-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.769C>T	p.Arg257Cys	missense_variant	7/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.640C>T	p.Arg214Cys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.769C>T	p.Arg257Cys	missense_variant	7/9	1	NM_001615.4	P1
ACTG2	ENST00000409624.1	c.769C>T	p.Arg257Cys	missense_variant	8/10	2		P1
ACTG2	ENST00000409731.7	c.640C>T	p.Arg214Cys	missense_variant	6/8	2
ACTG2	ENST00000438902.6	c.*834C>T		3_prime_UTR_variant, NMD_transcript_variant	8/10	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450726 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720108

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.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral myopathy 1 Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 07, 2021	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Mar 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2022	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) -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	- -

Visceral neuropathy, familial, 3, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Suma Genomics

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2014

- -

Chronic intestinal pseudoobstruction;C1855311:Megacystis Pathogenic:1

Pathogenic, no assertion criteria provided

research

UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini

May 02, 2015

- -

Chronic intestinal pseudoobstruction Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
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	D
GERP RS		4.7
Varity_R		0.91
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: rs587777387; hg19: chr2-74141962;