chr12-1801133-C-T

Position:

• chr12-1801133-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172364.5(CACNA2D4):​c.2793-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,612,218 control chromosomes in the GnomAD database, including 742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (43 hom., cov: 33)
  • Exomes 𝑓: 0.027 (699 hom.)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0980

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=-0.85).
• BP6: Variant 12-1801133-C-T is Benign according to our data. Variant chr12-1801133-C-T is described in ClinVar as [Benign]. Clinvar id is 262817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1801133-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3362/152242) while in subpopulation NFE AF= 0.0303 (2063/67994). AF 95% confidence interval is 0.0293. There are 43 homozygotes in gnomad4. There are 1629 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2793-15G>A		intron_variant		ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2793-15G>A		intron_variant		1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2793-15G>A		intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2718-15G>A		intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2601-15G>A		intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2601-15G>A		intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.237-15G>A		intron_variant		5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.228-15G>A		intron_variant		5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.183-15G>A		intron_variant		2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*977-15G>A		intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.562-15G>A		intron_variant		1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.112-15G>A		intron_variant		1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.157-15G>A		intron_variant		5		ENSP00000467333.1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3353 AN: 152124 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.00801

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0227 AC: 5646 AN: 248790 Hom.: 106 AF XY: 0.0234 AC XY: 3161 AN XY: 135038

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0555

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0151

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0300

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0269 AC: 39319 AN: 1459976 Hom.: 699 Cov.: 31 AF XY: 0.0266 AC XY: 19314 AN XY: 726408

Gnomad4 AFR exome AF: 0.00810

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0293

Gnomad4 OTH exome AF: 0.0295

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152242 Hom.: 43 Cov.: 33 AF XY: 0.0219 AC XY: 1629 AN XY: 74440

Gnomad4 AFR AF: 0.00825

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0603

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0303

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0298 Hom.: 12

Bravo AF: 0.0210

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 4 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.54
DANN	Benign	0.53

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: rs147575839; hg19: chr12-1910299;