rs12811035

Variant names:

• chr12-1792380-A-C
• rs12811035
• NM_172364.5:c.*1275T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172364.5(CACNA2D4):​c.*1275T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,262 control chromosomes in the GnomAD database, including 1,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1843 hom., cov: 34)
  • Exomes 𝑓: 0.091 (0 hom.)
• Consequence: CACNA2D4 NM_172364.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.02
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-1792380-A-C is Benign according to our data. Variant chr12-1792380-A-C is described in ClinVar as Benign. ClinVar VariationId is 307808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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.*1275T>G		3_prime_UTR	Exon 38 of 38	NP_758952.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.*1275T>G		3_prime_UTR	Exon 38 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000537784.5	TSL:1	n.*1882T>G		non_coding_transcript_exon	Exon 15 of 15	ENSP00000440231.2	X6RLU5
	CACNA2D4	ENST00000537784.5	TSL:1	n.*1882T>G		3_prime_UTR	Exon 15 of 15	ENSP00000440231.2	X6RLU5

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20982 AN: 152122 Hom.: 1844 Cov.: 34

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.0909 AC: 2 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.143 AC XY: 2 AN XY: 14

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.100 AC: 1 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.138 AC: 20995 AN: 152240 Hom.: 1843 Cov.: 34 AF XY: 0.137 AC XY: 10181 AN XY: 74440

African (AFR) AF: 0.0427 AC: 1776 AN: 41548

American (AMR) AF: 0.225 AC: 3449 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3472

East Asian (EAS) AF: 0.170 AC: 877 AN: 5174

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4826

European-Finnish (FIN) AF: 0.0857 AC: 909 AN: 10608

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11626 AN: 67994

Other (OTH) AF: 0.170 AC: 359 AN: 2116

Alfa AF: 0.161 Hom.: 786

Bravo AF: 0.144

Asia WGS AF: 0.184 AC: 636 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.057
DANN	Benign	0.73
PhyloP100		-3.0
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: rs12811035; hg19: chr12-1901546;