15-34794648-G-T

Variant names:

• chr15-34794648-G-T
• rs76013827
• NM_005159.5:c.129+32C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005159.5(ACTC1):​c.129+32C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,604,810 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: ACTC1 NM_005159.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.789

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-34794648-G-T is Benign according to our data. Variant chr15-34794648-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 259653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34794648-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1631/151944) while in subpopulation AFR AF= 0.0374 (1541/41194). AF 95% confidence interval is 0.0359. There are 39 homozygotes in gnomad4. There are 787 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.129+32C>A		intron_variant	Intron 2 of 6	ENST00000290378.6	NP_005150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.129+32C>A		intron_variant	Intron 2 of 6	1	NM_005159.5	ENSP00000290378.4
GJD2-DT	ENST00000503496.6	n.300-15848G>T		intron_variant	Intron 2 of 2	2
ACTC1	ENST00000560563.2	n.235+32C>A		intron_variant	Intron 2 of 5	2
GJD2-DT	ENST00000671663.1	n.95-15848G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 151830 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00274 AC: 642 AN: 234502 Hom.: 11 AF XY: 0.00217 AC XY: 279 AN XY: 128596

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000674

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00122 AC: 1771 AN: 1452866 Hom.: 31 Cov.: 31 AF XY: 0.00109 AC XY: 786 AN XY: 721722

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000702

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 151944 Hom.: 39 Cov.: 32 AF XY: 0.0106 AC XY: 787 AN XY: 74308

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00449 Hom.: 0

Bravo AF: 0.0126

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.62

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: rs76013827; hg19: chr15-35086849;