15-34794648-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 259653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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

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

GnomAD2 exomes AF: 0.00274 AC: 642 AN: 234502 AF XY: 0.00217

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 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

African (AFR) AF: 0.0382 AC: 1274 AN: 33344

American (AMR) AF: 0.00312 AC: 138 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39532

South Asian (SAS) AF: 0.0000702 AC: 6 AN: 85428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52090

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5746

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1106876

Other (OTH) AF: 0.00295 AC: 177 AN: 59950

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

African (AFR) AF: 0.0374 AC: 1541 AN: 41194

American (AMR) AF: 0.00385 AC: 59 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

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
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism

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: rs76013827; hg19: chr15-35086849;