2-73914698-G-T

Variant names:

• chr2-73914698-G-T
• rs1553396458
• NM_001615.4:c.632G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001615.4(ACTG2):​c.632G>T​(p.Arg211Leu) 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. 13/22 in silico tools predict a damaging 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. R211Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73914698-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495145.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, 0.955
• PP5: Variant 2-73914698-G-T is Pathogenic according to our data. Variant chr2-73914698-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1804921.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG2	NM_001615.4	c.632G>T	p.Arg211Leu	missense_variant	Exon 7 of 9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.503G>T	p.Arg168Leu	missense_variant	Exon 6 of 8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.632G>T	p.Arg211Leu	missense_variant	Exon 7 of 9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Visceral myopathy 1 Pathogenic:1

Jun 24, 2022

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 (MIM#155310), a phenotype which encompasses megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS) 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 leucine. (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 and highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.Arg211Gln variant has been reported in three individuals with inherited megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS) or chronic intestinal pseudoobstruction (CIPO) (ClinVar; PMIDs: 29387497, 31769566). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	.;H;H
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.95
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		0.79		.;Loss of methylation at K216 (P = 0.0489);Loss of methylation at K216 (P = 0.0489);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.96
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs1553396458; hg19: chr2-74141825; COSMIC: COSV100609340; COSMIC: COSV100609340;