rs2229952

chr7-82038152-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000722.4(CACNA2D1):c.963G>A(p.Ala321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,612,970 control chromosomes in the GnomAD database, including 1,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (160 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1390 hom.)
• Consequence: CACNA2D1 NM_000722.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.78

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=-0.27).
• BP6: Variant 7-82038152-C-T is Benign according to our data. Variant chr7-82038152-C-T is described in ClinVar as [Benign]. Clinvar id is 256769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82038152-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0347 (5288/152196) while in subpopulation NFE AF= 0.0489 (3326/68014). AF 95% confidence interval is 0.0475. There are 160 homozygotes in gnomad4. There are 2611 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 5282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.963G>A	p.Ala321=	synonymous_variant	11/39	ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.963G>A	p.Ala321=	synonymous_variant	11/39	1	NM_000722.4

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5282 AN: 152080 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.00824

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.0698

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0489

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0375 AC: 9410 AN: 251086 Hom.: 242 AF XY: 0.0389 AC XY: 5276 AN XY: 135704

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0527

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0306

Gnomad FIN exome AF: 0.0676

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0400 AC: 58379 AN: 1460774 Hom.: 1390 Cov.: 30 AF XY: 0.0403 AC XY: 29268 AN XY: 726708

Gnomad4 AFR exome AF: 0.00634

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0342

Gnomad4 FIN exome AF: 0.0674

Gnomad4 NFE exome AF: 0.0422

Gnomad4 OTH exome AF: 0.0362

GnomAD4 genome AF: 0.0347 AC: 5288 AN: 152196 Hom.: 160 Cov.: 33 AF XY: 0.0351 AC XY: 2611 AN XY: 74416

Gnomad4 AFR AF: 0.00824

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0325

Gnomad4 FIN AF: 0.0698

Gnomad4 NFE AF: 0.0489

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0455 Hom.: 90

Bravo AF: 0.0285

Asia WGS AF: 0.0130 AC: 47 AN: 3478

EpiCase AF: 0.0435

EpiControl AF: 0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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. -

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 11, 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	-0.27
Cadd	Benign	2.2
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229952; hg19: chr7-81667468;