chr12-1793763-C-T

Position:

chr12-1793763-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172364.5(CACNA2D4):c.3310-4G>A 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 0.0128 in 1,611,862 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 113 hom., cov: 32)

Exomes 𝑓: 0.011 ( 429 hom. )

Consequence

CACNA2D4
NM_172364.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005592

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.04

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-1793763-C-T is Benign according to our data. Variant chr12-1793763-C-T is described in ClinVar as [Benign]. Clinvar id is 262818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5 linkuse as main transcript	c.3310-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.3310-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_172364.5	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4114

AN:

152194

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0774

Gnomad SAS

AF:

0.0436

Gnomad FIN

AF:

0.0739

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0262

AC:

6397

AN:

244554

Hom.:

190

AF XY:

0.0251

AC XY:

3351

AN XY:

133450

show subpopulations

Gnomad AFR exome

AF:

0.0536

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.000604

Gnomad EAS exome

AF:

0.0744

Gnomad SAS exome

AF:

0.0404

Gnomad FIN exome

AF:

0.0754

Gnomad NFE exome

AF:

0.00451

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0114

AC:

16575

AN:

1459550

Hom.:

429

Cov.:

AF XY:

0.0120

AC XY:

8732

AN XY:

726148

show subpopulations

Gnomad4 AFR exome

AF:

0.0538

Gnomad4 AMR exome

AF:

0.0230

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.0675

Gnomad4 SAS exome

AF:

0.0407

Gnomad4 FIN exome

AF:

0.0704

Gnomad4 NFE exome

AF:

0.00260

Gnomad4 OTH exome

AF:

0.0152

GnomAD4 genome

AF:

0.0272

AC:

4136

AN:

152312

Hom.:

113

Cov.:

AF XY:

0.0303

AC XY:

2255

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0519

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0777

Gnomad4 SAS

AF:

0.0433

Gnomad4 FIN

AF:

0.0739

Gnomad4 NFE

AF:

0.00384

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.0246

Asia WGS

AF:

0.0890

AC:

307

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Retinal cone dystrophy 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

-0.86

CADD

Benign

0.14

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000056

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over