7-81974555-GAAAA-GAAA

Position:

• chr7-81974555-GAAAA-GAAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000722.4(CACNA2D1):​c.1956-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,344,872 control chromosomes in the GnomAD database, including 4 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 0.0025 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.195

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]

CACNA2D1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 7-81974555-GA-G is Benign according to our data. Variant chr7-81974555-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 416578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81974555-GA-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.1956-4delT		splice_region_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.1956-4delT		splice_region_variant, intron_variant		1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000443883.2	c.1992-4delT		splice_region_variant, intron_variant		5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.1836-4delT		splice_region_variant, intron_variant				ENSP00000516190.1
CACNA2D1	ENST00000705961.1	c.1722-4delT		splice_region_variant, intron_variant				ENSP00000516189.1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 364 AN: 147524 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000299

Gnomad OTH AF: 0.00394

GnomAD3 exomes AF: 0.000814 AC: 158 AN: 194206 Hom.: 1 AF XY: 0.000589 AC XY: 62 AN XY: 105240

Gnomad AFR exome AF: 0.00916

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000704

Gnomad SAS exome AF: 0.0000415

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000701

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000318 AC: 381 AN: 1197266 Hom.: 2 Cov.: 18 AF XY: 0.000282 AC XY: 171 AN XY: 605532

Gnomad4 AFR exome AF: 0.00764

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000545

Gnomad4 SAS exome AF: 0.0000779

Gnomad4 FIN exome AF: 0.0000399

Gnomad4 NFE exome AF: 0.0000542

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00249 AC: 367 AN: 147606 Hom.: 2 Cov.: 30 AF XY: 0.00202 AC XY: 145 AN XY: 71768

Gnomad4 AFR AF: 0.00724

Gnomad4 AMR AF: 0.00440

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000299

Gnomad4 OTH AF: 0.00390

Alfa AF: 0.000258 Hom.: 35

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2017

This alteration is classified as 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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3083235; hg19: chr7-81603871;