12-1792295-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_172364.5(CACNA2D4):c.*1360G>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 0.0265 in 152,280 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (109 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA2D4 NM_172364.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.96

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-1792295-C-T is Benign according to our data. Variant chr12-1792295-C-T is described in ClinVar as [Benign]. Clinvar id is 307805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.*1360G>A		3_prime_UTR_variant	38/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.*1360G>A		3_prime_UTR_variant	38/38	1	NM_172364.5	P2
CACNA2D4	ENST00000537784.5	c.*1967G>A		3_prime_UTR_variant, NMD_transcript_variant	15/15	1
CACNA2D4	ENST00000280663.12	n.5604G>A		non_coding_transcript_exon_variant	36/36	2

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4021 AN: 152162 Hom.: 109 Cov.: 34

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0783

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.0739

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.0201

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0265 AC: 4043 AN: 152280 Hom.: 109 Cov.: 34 AF XY: 0.0298 AC XY: 2219 AN XY: 74464

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.0786

Gnomad4 SAS AF: 0.0437

Gnomad4 FIN AF: 0.0739

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00685 Hom.: 15

Bravo AF: 0.0238

Asia WGS AF: 0.0890 AC: 307 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.40
Dann	Benign	0.63

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: rs2041139; hg19: chr12-1901461;