rs121912677

Positions:

• chr15-34793326-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_005159.5(ACTC1):​c.373A>G​(p.Met125Val) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M125T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

Genes affected

ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTC1. . Gene score misZ 4.5244 (greater than the threshold 3.09). Trascript score misZ 6.3156 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 15-34793326-T-C is Pathogenic according to our data. Variant chr15-34793326-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 18327.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34793326-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTC1	NM_005159.5	c.373A>G	p.Met125Val	missense_variant	3/7	ENST00000290378.6
GJD2-DT	NR_120329.1	n.299+15895T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTC1	ENST00000290378.6	c.373A>G	p.Met125Val	missense_variant	3/7	1	NM_005159.5	P1
GJD2-DT	ENST00000671663.1	n.95-17170T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial septal defect 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.033	D
Polyphen		0.011	B
Vest4		0.86
MutPred		0.73		Gain of catalytic residue at M125 (P = 0.0265);
MVP		1.0
MPC		1.6
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121912677; hg19: chr15-35085527;