NM_001615.4:c.442C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

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 Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACTG2
NM_001615.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.03

Publications

12 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 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001615.4

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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 180620.Status of the report is no_assertion_criteria_provided, 0 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, 0.98

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 VariationId is 1177291.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.442C>T	p.Arg148Cys	missense_variant	Exon 5 of 9	ENST00000345517.8	NP_001606.1	P63267-1
ACTG2	NM_001199893.2 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 4 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.442C>T	p.Arg148Cys	missense_variant	Exon 5 of 9	1	NM_001615.4	ENSP00000295137.3		P63267-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251416

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460712

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110946

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Visceral myopathy 1

Pathogenic:2

May 20, 2025

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 06, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

.;M;M

PhyloP100

6.0

PrimateAI

Pathogenic

0.92

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

GERP RS

4.7

Varity_R

0.92

gMVP

0.99

Mutation Taster

=62/38

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over