7-82066526-TAAAAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000722.4(CACNA2D1):c.659-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 111,628 control chromosomes in the GnomAD database, including 240 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (240 hom., cov: 27)
  • Exomes 𝑓: 0.31 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA2D1 NM_000722.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04

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 -16 ACMG points.

• BP6: Variant 7-82066526-TA-T is Benign according to our data. Variant chr7-82066526-TA-T is described in ClinVar as [Benign]. Clinvar id is 416576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82066526-TA-T is described in Lovd as [Benign]. Variant chr7-82066526-TA-T is described in Lovd as [Likely_benign]. Variant chr7-82066526-TA-T is described in Lovd as [Benign]. Variant chr7-82066526-TA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.659-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356860.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.659-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 5259 AN: 111650 Hom.: 240 Cov.: 27

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0211

Gnomad SAS AF: 0.00428

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00736

Gnomad OTH AF: 0.0288

GnomAD3 exomes AF: 0.337 AC: 30495 AN: 90532 Hom.: 1 AF XY: 0.340 AC XY: 16508 AN XY: 48522

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.342

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.311 AC: 346937 AN: 1116808 Hom.: 2 Cov.: 0 AF XY: 0.310 AC XY: 171845 AN XY: 553670

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.306

Gnomad4 EAS exome AF: 0.313

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.307

GnomAD4 genome AF: 0.0472 AC: 5266 AN: 111628 Hom.: 240 Cov.: 27 AF XY: 0.0482 AC XY: 2551 AN XY: 52924

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0212

Gnomad4 SAS AF: 0.00460

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.00737

Gnomad4 OTH AF: 0.0294

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

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: rs370103843; hg19: chr7-81695842;