7-82066526-TAAAAA-TAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000722.4(CACNA2D1):c.659-3_659-2insTT 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 0.00571 in 1,444,058 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 27)
  • Exomes 𝑓: 0.0056 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 7-82066526-T-TAA is Benign according to our data. Variant chr7-82066526-T-TAA is described in ClinVar as [Likely_benign]. Clinvar id is 1284710.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 819 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.659-3_659-2insTT		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.659-3_659-2insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 819 AN: 111742 Hom.: 5 Cov.: 27

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000514

Gnomad SAS AF: 0.00656

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00556 AC: 503 AN: 90532 Hom.: 1 AF XY: 0.00589 AC XY: 286 AN XY: 48522

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00616

Gnomad SAS exome AF: 0.00611

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.00558 AC: 7428 AN: 1332338 Hom.: 2 Cov.: 0 AF XY: 0.00552 AC XY: 3635 AN XY: 658300

Gnomad4 AFR exome AF: 0.00368

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00204

Gnomad4 EAS exome AF: 0.00210

Gnomad4 SAS exome AF: 0.00616

Gnomad4 FIN exome AF: 0.00772

Gnomad4 NFE exome AF: 0.00577

Gnomad4 OTH exome AF: 0.00567

GnomAD4 genome AF: 0.00732 AC: 818 AN: 111720 Hom.: 5 Cov.: 27 AF XY: 0.00774 AC XY: 410 AN XY: 52974

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000517

Gnomad4 SAS AF: 0.00603

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0124

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2019

This alteration is classified as likely 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

Splicing

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;