rs1553396458

chr2-73914698-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001615.4(ACTG2):c.632G>A(p.Arg211Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,226 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 8 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-T is described in ClinVar as [Pathogenic]. Clinvar id is 1804921.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACTG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 2-73914698-G-A is Pathogenic according to our data. Variant chr2-73914698-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495145.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}. Variant chr2-73914698-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG2	NM_001615.4	c.632G>A	p.Arg211Gln	missense_variant	7/9	ENST00000345517.8
ACTG2	NM_001199893.2	c.503G>A	p.Arg168Gln	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG2	ENST00000345517.8	c.632G>A	p.Arg211Gln	missense_variant	7/9	1	NM_001615.4	P1
ACTG2	ENST00000409624.1	c.632G>A	p.Arg211Gln	missense_variant	8/10	2		P1
ACTG2	ENST00000409731.7	c.503G>A	p.Arg168Gln	missense_variant	6/8	2
ACTG2	ENST00000438902.6	c.*697G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440226 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715836

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Visceral myopathy 1 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Insufficient data for genotype-phenotype correlations -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Oct 17, 2016	- -
Pathogenic, no assertion criteria provided	case-control	Wangler Lab, Baylor College of Medicine	Oct 04, 2019	Identified as a de novo event in our clinical cohort of MMIHS -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 28, 2023

Identified in two individuals from the same family with CIPO or MMIHS (Whittington et al., 2017); 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: 29387497) -

ACTG2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

The ACTG2 c.632G>A variant is predicted to result in the amino acid substitution p.Arg211Gln. This variant was reported in an individual with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (Table S2 and S3, ID FAM53-1 or Fam53, maternally-inherited, Assia Batzir et al. 2019. PubMed ID: 31769566) and was also reported in an individual with chronic intestinal pseudoobstruction and in her fetus with MMIHS (Whittington et al. 2017. PubMed ID: 29387497). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.81
MutPred		0.72		.;Gain of ubiquitination at K216 (P = 0.0635);Gain of ubiquitination at K216 (P = 0.0635);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.92
gMVP		0.90

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: rs1553396458; hg19: chr2-74141825;