rs869312168

Variant names:

• chr2-73901424-G-A
• rs869312168
• NM_001615.4:c.113G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.93
• Publications: 9 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 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 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, 0.939
• PP5: Variant 2-73901424-G-A is Pathogenic according to our data. Variant chr2-73901424-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217521.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG2	NM_001615.4	c.113G>A	p.Arg38His	missense_variant	Exon 2 of 9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.113G>A	p.Arg38His	missense_variant	Exon 2 of 8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.113G>A	p.Arg38His	missense_variant	Exon 2 of 9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461724 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic intestinal pseudoobstruction 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
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	D
LIST_S2	Benign	0.81	T;.;T;T;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.;M
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
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	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.84
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312168; hg19: chr2-74128551; COSMIC: COSV61828224;