rs202022529

Positions:

• chr12-1800379-C-G
• chr12-1800379-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.2921+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,880 control chromosomes in the GnomAD database, including 3 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: CACNA2D4 NM_172364.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004731
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.332

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=-0.81).
• BP6: Variant 12-1800379-C-G is Benign according to our data. Variant chr12-1800379-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 96534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00247 (376/152296) while in subpopulation AFR AF= 0.00859 (357/41542). AF 95% confidence interval is 0.00786. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2921+7G>C		splice_region_variant, intron_variant		ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3	c.2858+7G>C		splice_region_variant, intron_variant			XP_011519343.1
CACNA2D4	XM_047429897.1	c.2849+7G>C		splice_region_variant, intron_variant			XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2921+7G>C		splice_region_variant, intron_variant		1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2921+7G>C		splice_region_variant, intron_variant		5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2846+7G>C		splice_region_variant, intron_variant		5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2729+7G>C		splice_region_variant, intron_variant		5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2729+7G>C		splice_region_variant, intron_variant		5		ENSP00000468530.1
CACNA2D4	ENST00000536846.6	c.359+7G>C		splice_region_variant, intron_variant		5		ENSP00000468167.1
CACNA2D4	ENST00000538027.6	c.356+7G>C		splice_region_variant, intron_variant		5		ENSP00000443038.2
CACNA2D4	ENST00000538450.5	c.311+7G>C		splice_region_variant, intron_variant		2		ENSP00000446341.1
CACNA2D4	ENST00000444595.6	n.*1105+7G>C		splice_region_variant, intron_variant		1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.*114+7G>C		splice_region_variant, intron_variant		1		ENSP00000440231.2
CACNA2D4	ENST00000545595.6	n.*114+7G>C		splice_region_variant, intron_variant		1		ENSP00000442329.2
CACNA2D4	ENST00000585385.5	n.*114+7G>C		splice_region_variant, intron_variant		5		ENSP00000467333.1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000619 AC: 153 AN: 247096 Hom.: 0 AF XY: 0.000477 AC XY: 64 AN XY: 134238

Gnomad AFR exome AF: 0.00873

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000270 AC: 394 AN: 1461584 Hom.: 2 Cov.: 32 AF XY: 0.000239 AC XY: 174 AN XY: 727092

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74460

Gnomad4 AFR AF: 0.00859

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.00300

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -

Retinal cone dystrophy 4 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.3
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs202022529; hg19: chr12-1909545;