NM_001615.4:c.118C>T

Variant names:

• chr2-73901429-C-T
• rs587777385
• NM_001615.4:c.118C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001615.4(ACTG2):​c.118C>T​(p.Arg40Cys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000583023: Missense variants at the same residue (R40H) and at nearby residue (M45T), have been reported in the Human Gene Mutation Database in association with MMIHS (Stenson et al., 2014), supporting the functional importance of this region of the protein.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ACTG2 NM_001615.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.93
• Publications: 7 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000583023: Missense variants at the same residue (R40H) and at nearby residue (M45T), have been reported in the Human Gene Mutation Database in association with MMIHS (Stenson et al., 2014), supporting the functional importance of this region of the protein.
• PM1: In a hotspot region, there are 4 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73901430-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132802.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, 0.962
• PP5: Variant 2-73901429-C-T is Pathogenic according to our data. Variant chr2-73901429-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001615.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG2	NM_001615.4	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 2 of 9	NP_001606.1	P63267-1
	ACTG2	NM_001199893.2		c.118C>T	p.Arg40Cys	missense	Exon 2 of 8	NP_001186822.1	P63267-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG2	ENST00000345517.8	TSL:1 MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 2 of 9	ENSP00000295137.3	P63267-1
	ACTG2	ENST00000409918.5	TSL:1	c.118C>T	p.Arg40Cys	missense	Exon 2 of 4	ENSP00000387182.1	B8ZZJ2
	ACTG2	ENST00000880128.1		c.118C>T	p.Arg40Cys	missense	Exon 2 of 10	ENSP00000550187.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Visceral myopathy 1 (3)
1	-	-	ACTG2-related disorder (1)
1	-	-	Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.96
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.84		Loss of sheet (P = 0.0181)
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.89
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587777385; hg19: chr2-74128556;