7-82066526-TAAAAA-TAAAAAA

Position:

• chr7-82066526-TAAAAA-TAAAAAA

Variant summary

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

The NM_000722.4(CACNA2D1):​c.659-3_659-2insT 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 0.0759 in 1,429,314 control chromosomes in the GnomAD database, including 1,400 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1394 hom., cov: 27)
  • Exomes 𝑓: 0.070 (6 hom.)
• 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-T-TA is Benign according to our data. Variant chr7-82066526-T-TA is described in ClinVar as [Benign]. Clinvar id is 416577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.659-3_659-2insT		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.659-3_659-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4	ENSP00000349320

Frequencies

GnomAD3 genomes AF: 0.150 AC: 16760 AN: 111620 Hom.: 1392 Cov.: 27

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.0968

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.0596 AC: 5397 AN: 90532 Hom.: 5 AF XY: 0.0588 AC XY: 2853 AN XY: 48522

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.0677

Gnomad SAS exome AF: 0.0589

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0696 AC: 91684 AN: 1317716 Hom.: 6 Cov.: 0 AF XY: 0.0685 AC XY: 44591 AN XY: 651366

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.0697

Gnomad4 EAS exome AF: 0.0690

Gnomad4 SAS exome AF: 0.0632

Gnomad4 FIN exome AF: 0.0395

Gnomad4 NFE exome AF: 0.0689

Gnomad4 OTH exome AF: 0.0737

GnomAD4 genome AF: 0.150 AC: 16763 AN: 111598 Hom.: 1394 Cov.: 27 AF XY: 0.149 AC XY: 7871 AN XY: 52906

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0968

Gnomad4 OTH AF: 0.160

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 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2017	- -

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;