7-81974555-GAAAA-GAAAAA

Variant names:

• chr7-81974555-G-GA
• rs3083235
• NM_000722.4:c.1956-4dupT

Variant summary

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

The NM_000722.4(CACNA2D1):​c.1956-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,332,840 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: 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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 7-81974555-G-GA is Benign according to our data. Variant chr7-81974555-G-GA is described in ClinVar as [Benign]. Clinvar id is 518634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.1956-4dupT		splice_region_variant, intron_variant	Intron 24 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.1956-4_1956-3insT		splice_region_variant, intron_variant	Intron 24 of 38	1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000443883.2	c.1992-4_1992-3insT		splice_region_variant, intron_variant	Intron 24 of 38	5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.1836-4_1836-3insT		splice_region_variant, intron_variant	Intron 23 of 37			ENSP00000516190.1
CACNA2D1	ENST00000705961.1	c.1722-4_1722-3insT		splice_region_variant, intron_variant	Intron 22 of 36			ENSP00000516189.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 201 AN: 147512 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000475

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.000642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000419

Gnomad OTH AF: 0.000492

GnomAD3 exomes AF: 0.00212 AC: 411 AN: 194206 Hom.: 1 AF XY: 0.00213 AC XY: 224 AN XY: 105240

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00324

Gnomad SAS exome AF: 0.00153

Gnomad FIN exome AF: 0.000958

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00301 AC: 3571 AN: 1185246 Hom.: 1 Cov.: 18 AF XY: 0.00285 AC XY: 1706 AN XY: 599354

Gnomad4 AFR exome AF: 0.00589

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00301

Gnomad4 EAS exome AF: 0.00263

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00164

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.00135 AC: 199 AN: 147594 Hom.: 1 Cov.: 30 AF XY: 0.00137 AC XY: 98 AN XY: 71756

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.000474

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00139

Gnomad4 SAS AF: 0.000644

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000419

Gnomad4 OTH AF: 0.000487

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Nov 06, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 20, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

CACNA2D1-related disorder Benign:1

Mar 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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: rs3083235; hg19: chr7-81603871;