rs147575839

Variant names:

• chr12-1801133-C-T
• rs147575839
• NM_172364.5:c.2793-15G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• CACNA2D4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287698 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.2793-15G>A		intron	N/A	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.2793-15G>A		intron	N/A	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2793-15G>A		intron	N/A	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2718-15G>A		intron	N/A	ENSP00000465372.1	K7EJY1

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

GnomAD2 exomes AF: 0.0227 AC: 5646 AN: 248790 AF XY: 0.0234

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 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

African (AFR) AF: 0.00810 AC: 271 AN: 33458

American (AMR) AF: 0.0168 AC: 750 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1476 AN: 26120

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.0150 AC: 1291 AN: 86226

European-Finnish (FIN) AF: 0.0201 AC: 1073 AN: 53378

Middle Eastern (MID) AF: 0.0339 AC: 195 AN: 5758

European-Non Finnish (NFE) AF: 0.0293 AC: 32477 AN: 1110316

Other (OTH) AF: 0.0295 AC: 1782 AN: 60306

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

African (AFR) AF: 0.00825 AC: 343 AN: 41556

American (AMR) AF: 0.0223 AC: 341 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 209 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4818

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0303 AC: 2063 AN: 67994

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0251 Hom.: 19

Bravo AF: 0.0210

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Retinal cone dystrophy 4 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.54
DANN	Benign	0.53
PhyloP100		0.098
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs147575839; hg19: chr12-1910299;