7-81974555-GAAAA-GAAAAAA

Variant names:

• chr7-81974555-G-GAA
• rs3083235
• NM_000722.4:c.1956-5_1956-4dupTT

Variant summary

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

The NM_000722.4(CACNA2D1):​c.1956-5_1956-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,342,172 control chromosomes in the GnomAD database, including 3,164 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (630 hom., cov: 30)
  • Exomes 𝑓: 0.076 (2534 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 -16 ACMG points.

• BP6: Variant 7-81974555-G-GAA is Benign according to our data. Variant chr7-81974555-G-GAA is described in ClinVar as [Benign]. Clinvar id is 215475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 13610 AN: 147442 Hom.: 631 Cov.: 30

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0990

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.192

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.0885 AC: 17192 AN: 194206 Hom.: 446 AF XY: 0.0857 AC XY: 9015 AN XY: 105240

Gnomad AFR exome AF: 0.0933

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.0598

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.0985

GnomAD4 exome AF: 0.0756 AC: 90358 AN: 1194648 Hom.: 2534 Cov.: 18 AF XY: 0.0749 AC XY: 45272 AN XY: 604160

Gnomad4 AFR exome AF: 0.0825

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0946

Gnomad4 EAS exome AF: 0.0925

Gnomad4 SAS exome AF: 0.0533

Gnomad4 FIN exome AF: 0.0405

Gnomad4 NFE exome AF: 0.0759

Gnomad4 OTH exome AF: 0.0825

GnomAD4 genome AF: 0.0923 AC: 13615 AN: 147524 Hom.: 630 Cov.: 30 AF XY: 0.0901 AC XY: 6466 AN XY: 71738

Gnomad4 AFR AF: 0.0940

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0990

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.0428

Gnomad4 NFE AF: 0.0921

Gnomad4 OTH AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 14, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 07, 2019

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. -

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: rs3083235; hg19: chr7-81603871;