7-82066526-TAAAAA-TA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000722.4(CACNA2D1):c.659-6_659-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,445,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome at 157 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D1	NM_000722.4	c.659-6_659-3del		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.659-6_659-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000722.4

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111740 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000201

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00173 AC: 157 AN: 90532 Hom.: 0 AF XY: 0.00157 AC XY: 76 AN XY: 48522

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.000857

Gnomad EAS exome AF: 0.00154

Gnomad SAS exome AF: 0.000925

Gnomad FIN exome AF: 0.000910

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000274 AC: 366 AN: 1334244 Hom.: 0 AF XY: 0.000285 AC XY: 188 AN XY: 659102

Gnomad4 AFR exome AF: 0.000885

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.000483

Gnomad4 SAS exome AF: 0.000702

Gnomad4 FIN exome AF: 0.000663

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.000255

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111740 Hom.: 0 Cov.: 27 AF XY: 0.0000378 AC XY: 2 AN XY: 52974

Gnomad4 AFR AF: 0.0000592

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000195

Gnomad4 NFE AF: 0.0000201

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00129 Hom.: 11

ClinVar

Not reported in ClinVar

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: rs370103843; hg19: chr7-81695842;