7-81974555-GAAAA-GAAAAAAA

Position:

• chr7-81974555-GAAAA-GAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000722.4(CACNA2D1):​c.1956-6_1956-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,343,674 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 7-81974555-G-GAAA is Benign according to our data. Variant chr7-81974555-G-GAAA is described in ClinVar as [Benign]. Clinvar id is 416571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.1956-6_1956-4dupTTT		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.1956-6_1956-4dupTTT		splice_region_variant, intron_variant		1	NM_000722.4	ENSP00000349320.3
CACNA2D1	ENST00000443883.2	c.1992-6_1992-4dupTTT		splice_region_variant, intron_variant		5		ENSP00000409374.2
CACNA2D1	ENST00000705962.1	c.1836-6_1836-4dupTTT		splice_region_variant, intron_variant				ENSP00000516190.1
CACNA2D1	ENST00000705961.1	c.1722-6_1722-4dupTTT		splice_region_variant, intron_variant				ENSP00000516189.1

Frequencies

GnomAD3 genomes AF: 0.000352 AC: 52 AN: 147530 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000599

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000598

Gnomad OTH AF: 0.00148

GnomAD3 exomes AF: 0.00127 AC: 246 AN: 194206 Hom.: 1 AF XY: 0.00108 AC XY: 114 AN XY: 105240

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00371

Gnomad ASJ exome AF: 0.000705

Gnomad EAS exome AF: 0.00148

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.000169

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00102 AC: 1224 AN: 1196144 Hom.: 2 Cov.: 18 AF XY: 0.000921 AC XY: 557 AN XY: 604944

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.000638

Gnomad4 EAS exome AF: 0.000901

Gnomad4 SAS exome AF: 0.000520

Gnomad4 FIN exome AF: 0.000558

Gnomad4 NFE exome AF: 0.000969

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000352 AC: 52 AN: 147530 Hom.: 0 Cov.: 30 AF XY: 0.000321 AC XY: 23 AN XY: 71676

Gnomad4 AFR AF: 0.000599

Gnomad4 AMR AF: 0.00129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000107

Gnomad4 NFE AF: 0.0000598

Gnomad4 OTH AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

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;