7-81991252-A-G

Position:

• chr7-81991252-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):​c.1735-6T>C variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000155 in 1,448,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.007774
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.19

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-81991252-A-G is Benign according to our data. Variant chr7-81991252-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 511685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.1735-6T>C		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.1735-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4
CACNA2D1	ENST00000443883.2	c.1792-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P1
CACNA2D1	ENST00000705961.1	c.1502-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CACNA2D1	ENST00000705962.1	c.1636-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 250850 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135596

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000748 AC: 97 AN: 1296132 Hom.: 0 Cov.: 20 AF XY: 0.0000627 AC XY: 41 AN XY: 653862

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000311

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74490

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000884

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2017

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

Dec 17, 2021

- -

CACNA2D1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as likely 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0078
dbscSNV1_RF	Benign	0.11
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: rs111772206; hg19: chr7-81620568;