3-54386694-G-GTTTTT

Variant names:

• chr3-54386694-G-GTTTTT
• rs62967361
• NM_018398.3:c.322-7_322-3dupTTTTT

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_018398.3(CACNA2D3):​c.322-7_322-3dupTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,404,780 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0029 (8 hom.)
• Consequence: CACNA2D3 NM_018398.3 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.255

Genes affected

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01831502 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGcgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 3-54386694-G-GTTTTT is Benign according to our data. Variant chr3-54386694-G-GTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 3033751.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D3	NM_018398.3	c.322-7_322-3dupTTTTT		splice_acceptor_variant, intron_variant	Intron 3 of 37	ENST00000474759.6	NP_060868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D3	ENST00000474759.6	c.322-21_322-20insTTTTT		intron_variant	Intron 3 of 37	1	NM_018398.3	ENSP00000419101.1

Frequencies

GnomAD3 genomes AF: 0.000241 AC: 32 AN: 132522 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000219

Gnomad SAS AF: 0.000499

Gnomad FIN AF: 0.000416

Gnomad MID AF: 0.00362

Gnomad NFE AF: 0.000261

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00290 AC: 3689 AN: 1272286 Hom.: 8 Cov.: 0 AF XY: 0.00292 AC XY: 1832 AN XY: 627408

Gnomad4 AFR exome AF: 0.00573

Gnomad4 AMR exome AF: 0.00444

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.00305

Gnomad4 SAS exome AF: 0.00495

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00268

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.000242 AC: 32 AN: 132494 Hom.: 1 Cov.: 21 AF XY: 0.000268 AC XY: 17 AN XY: 63462

Gnomad4 AFR AF: 0.000248

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000220

Gnomad4 SAS AF: 0.000502

Gnomad4 FIN AF: 0.000416

Gnomad4 NFE AF: 0.000261

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CACNA2D3-related disorder Benign:1

Jan 21, 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62967361; hg19: chr3-54420721;