7-82066526-TAAAAA-TAAA

Position:

• chr7-82066526-TAAAAA-TAAA

Variant summary

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

The NM_000722.4(CACNA2D1):​c.659-4_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 0.0299 in 1,348,660 control chromosomes in the GnomAD database, including 56 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (55 hom., cov: 27)
  • Exomes 𝑓: 0.031 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23

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-TAA-T is Benign according to our data. Variant chr7-82066526-TAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 518490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82066526-TAA-T is described in Lovd as [Benign]. Variant chr7-82066526-TAA-T is described in Lovd as [Benign]. Variant chr7-82066526-TAA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.659-4_659-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.659-4_659-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4	ENSP00000349320

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 2346 AN: 111648 Hom.: 55 Cov.: 27

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00650

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000257

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00488

Gnomad MID AF: 0.00909

Gnomad NFE AF: 0.000602

Gnomad OTH AF: 0.0184

GnomAD3 exomes AF: 0.0775 AC: 7016 AN: 90532 Hom.: 3 AF XY: 0.0777 AC XY: 3771 AN XY: 48522

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.0760

Gnomad EAS exome AF: 0.0757

Gnomad SAS exome AF: 0.0798

Gnomad FIN exome AF: 0.0531

Gnomad NFE exome AF: 0.0667

Gnomad OTH exome AF: 0.0756

GnomAD4 exome AF: 0.0306 AC: 37912 AN: 1237034 Hom.: 1 AF XY: 0.0318 AC XY: 19387 AN XY: 610022

Gnomad4 AFR exome AF: 0.0892

Gnomad4 AMR exome AF: 0.0745

Gnomad4 ASJ exome AF: 0.0455

Gnomad4 EAS exome AF: 0.0431

Gnomad4 SAS exome AF: 0.0563

Gnomad4 FIN exome AF: 0.0507

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0210 AC: 2347 AN: 111626 Hom.: 55 Cov.: 27 AF XY: 0.0212 AC XY: 1124 AN XY: 52912

Gnomad4 AFR AF: 0.0649

Gnomad4 AMR AF: 0.00650

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000258

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00488

Gnomad4 NFE AF: 0.000602

Gnomad4 OTH AF: 0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2015

This alteration is classified as likely benign based on a combination of the following: 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. -

CACNA2D1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;