12-1792268-C-T

Position:

• chr12-1792268-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172364.5(CACNA2D4):​c.*1387G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,188 control chromosomes in the GnomAD database, including 16,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16608 hom., cov: 33)
  • Exomes 𝑓: 0.67 (5 hom.)
• Consequence: CACNA2D4 NM_172364.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.792

Genes affected

CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) 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]

CACNA2D4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-1792268-C-T is Benign according to our data. Variant chr12-1792268-C-T is described in ClinVar as [Benign]. Clinvar id is 307803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.*1387G>A		3_prime_UTR_variant	38/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722	c.*1387G>A		3_prime_UTR_variant	38/38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000537784.5	n.*1994G>A		non_coding_transcript_exon_variant	15/15	1		ENSP00000440231.2
CACNA2D4	ENST00000537784.5	n.*1994G>A		3_prime_UTR_variant	15/15	1		ENSP00000440231.2
CACNA2D4	ENST00000280663.12	n.5631G>A		non_coding_transcript_exon_variant	36/36	2

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66413 AN: 152046 Hom.: 16606 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.667 AC: 16 AN: 24 Hom.: 5 Cov.: 0 AF XY: 0.650 AC XY: 13 AN XY: 20

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.436 AC: 66419 AN: 152164 Hom.: 16608 Cov.: 33 AF XY: 0.437 AC XY: 32469 AN XY: 74378

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.482

Gnomad4 SAS AF: 0.451

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.564

Gnomad4 OTH AF: 0.424

Alfa AF: 0.543 Hom.: 36119

Bravo AF: 0.414

Asia WGS AF: 0.424 AC: 1479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.16
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13219; hg19: chr12-1901434;