rs1229502

chr7-81959320-G-Achr7-81959320-G-Cchr7-81959320-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000722.4(CACNA2D1):c.3114C>T(p.Pro1038=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,606,426 control chromosomes in the GnomAD database, including 72,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5505 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66514 hom.)
• Consequence: CACNA2D1 NM_000722.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.215

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 7-81959320-G-A is Benign according to our data. Variant chr7-81959320-G-A is described in ClinVar as [Benign]. Clinvar id is 256767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81959320-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.3114C>T	p.Pro1038=	synonymous_variant	38/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.3114C>T	p.Pro1038=	synonymous_variant	38/39	1	NM_000722.4
CACNA2D1	ENST00000443883.2	c.3150C>T	p.Pro1050=	synonymous_variant	38/39	5		P1
CACNA2D1	ENST00000705962.1	c.2994C>T	p.Pro998=	synonymous_variant	37/38
CACNA2D1	ENST00000705961.1	c.2883C>T	p.Pro961=	synonymous_variant	36/37

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38638 AN: 151658 Hom.: 5504 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.291 AC: 72862 AN: 250768 Hom.: 11027 AF XY: 0.292 AC XY: 39629 AN XY: 135524

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.237

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.299 AC: 435612 AN: 1454650 Hom.: 66514 Cov.: 31 AF XY: 0.300 AC XY: 217288 AN XY: 724108

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.255 AC: 38636 AN: 151776 Hom.: 5505 Cov.: 32 AF XY: 0.256 AC XY: 18954 AN XY: 74154

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.287

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.273

Alfa AF: 0.301 Hom.: 5142

Bravo AF: 0.250

Asia WGS AF: 0.215 AC: 748 AN: 3478

EpiCase AF: 0.310

EpiControl AF: 0.312

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2017

- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	11
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: rs1229502; hg19: chr7-81588636; COSMIC: COSV62374686; COSMIC: COSV62374686;