ENST00000558707.4:n.680C>T

Variant names:

• chr15-34790165-C-T
• rs886051088
• ENST00000558707.4:n.680C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000558707.4(GJD2-DT):​n.680C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GJD2-DT ENST00000558707.4 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:5
• Conservation: PhyloP100: 0.0740
• Publications: 1 publications found

Genes affected

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

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]

ACTC1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• atrial septal defect 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1R

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arthrogryposis syndrome

  Inheritance: AD Classification: MODERATE Submitted by: University of Washington Center for Rare Disease Research (UW-CRDR)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558707.4. 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
	GJD2-DT	NR_120329.1		n.299+12734C>T		intron	N/A
	ACTC1	NM_005159.5	MANE Select	c.*247G>A		downstream_gene	N/A	NP_005150.1	P68032
	ACTC1	NM_001406482.1		c.*247G>A		downstream_gene	N/A	NP_001393411.1	P68032

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJD2-DT	ENST00000558707.4	TSL:3	n.680C>T		non_coding_transcript_exon	Exon 3 of 3
	ACTC1	ENST00000560563.2	TSL:2	n.2281G>A		non_coding_transcript_exon	Exon 6 of 6
	GJD2-DT	ENST00000693120.3		n.519C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 315174 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 168372

African (AFR) AF: 0.00 AC: 0 AN: 9310

American (AMR) AF: 0.00 AC: 0 AN: 15430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9334

East Asian (EAS) AF: 0.00 AC: 0 AN: 19308

South Asian (SAS) AF: 0.00 AC: 0 AN: 42028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1324

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 185318

Other (OTH) AF: 0.00 AC: 0 AN: 17482

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Atrial septal defect (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Familial restrictive cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Left ventricular noncompaction cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.67
PhyloP100		0.074

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

Other links and lift over

dbSNP: rs886051088; hg19: chr15-35082366;