2-73909130-C-T

Position:

• chr2-73909130-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001615.4(ACTG2):​c.442C>T​(p.Arg148Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R148L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.03

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 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 chr2-73909131-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTG2. . Gene score misZ 3.3487 (greater than the threshold 3.09). Trascript score misZ 4.3482 (greater than threshold 3.09). GenCC has associacion of gene with visceral myopathy 1, familial visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 2-73909130-C-T is Pathogenic according to our data. Variant chr2-73909130-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1177291.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG2	NM_001615.4	c.442C>T	p.Arg148Cys	missense_variant	5/9	ENST00000345517.8	NP_001606.1
ACTG2	NM_001199893.2	c.313C>T	p.Arg105Cys	missense_variant	4/8		NP_001186822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG2	ENST00000345517.8	c.442C>T	p.Arg148Cys	missense_variant	5/9	1	NM_001615.4	ENSP00000295137.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460712 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726772

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Visceral myopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

-

The p.Arg148Cys replaces the arginine with cysteine at position 148 of the protein. This variant has been observed once in large population studies (1 of 251,416 alleles; gnomAD v2.1.1). The p.Arg148Cys variant has been reported in one individual with intestinal pseudo-obstruction, gastrointestinal dysmotility and constipation (PMID: 37288276). The variant was reported to be inherited from an affected father, but no clinical details were provided. Different ACTG2 missense variants at the same position (p.Arg148Leu and p.Arg148Ser) have also been reported in the medical literature. The p.Arg148Leu variant was reported in one family with multiple individuals diagnosed with chronic intestinal pseudo-obstruction (PMID: 29781137). The p.Arg148Leu was also reported as a de novo change in an individual with pediatric intestinal pseudo-obstruction (PMID: 32810037). The p.Arg148Ser variant has been reported in multiple affected individuals, including one family where the variant was shown to segregate with the visceral myopathy phenotype (PMID: 22960657, PMID: 24777424). -

Intestinal obstruction Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 06, 2021

A heterozygous, likely pathogenic variant was identified in exon 5 of the ACTG2 gene (NM_001615.3:c.442C>T, p.Arg148Cys, chr2:g.74136257C>T ). The p.Arg148Cys replaces the arginine with cysteine at position 148 of the protein. This variant has been observed in a single allele in the Genome Aggregation Database (1 of 251,416 alleles; v2.1.1). This variant has not been reported in the medical literature, but different missense variants at the same position (p.Arg148Leu and p.Arg148Ser) have been reported as pathogenic. The p.Arg148Leu variant is reported in a single family with multiple individuals (n=4) diagnosed with chronic intestinal pseudo-obstruction (PMID: 29781137). These individuals were aged 20s-50s and all 4 reported symptoms of abdominal pain, distension, nausea, vomiting, and diarrhea. The p.Arg148Ser variant has been reported in at least 2 unrelated individuals, both with a positive family history of visceral myopathy (PMID: 22960657, 24777424). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.96
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.81
MutPred		0.90		.;Loss of methylation at R148 (P = 0.0112);Loss of methylation at R148 (P = 0.0112);
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.92
gMVP		0.99

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: rs587777383; hg19: chr2-74136257; COSMIC: COSV61827980; COSMIC: COSV61827980;