12-1792268-C-T

Variant names:

• chr12-1792268-C-T
• rs13219
• NM_172364.5:c.*1387G>A

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.*1387G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,188 control chromosomes in the GnomAD database, including 16,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16608 hom., cov: 33)
  • Exomes 𝑓: 0.67 (5 hom.)
• Consequence: CACNA2D4 NM_172364.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.792
• Publications: 16 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: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 12-1792268-C-T is Benign according to our data. Variant chr12-1792268-C-T is described in ClinVar as Benign. ClinVar VariationId is 307803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.559 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.*1387G>A		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.*1387G>A		3_prime_UTR	Exon 38 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000537784.5	TSL:1	n.*1994G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000440231.2	X6RLU5
	CACNA2D4	ENST00000537784.5	TSL:1	n.*1994G>A		3_prime_UTR	Exon 15 of 15	ENSP00000440231.2	X6RLU5

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66413 AN: 152046 Hom.: 16606 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.667 AC: 16 AN: 24 Hom.: 5 Cov.: 0 AF XY: 0.650 AC XY: 13 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 6 AN: 8

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.625 AC: 5 AN: 8

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.436 AC: 66419 AN: 152164 Hom.: 16608 Cov.: 33 AF XY: 0.437 AC XY: 32469 AN XY: 74378

African (AFR) AF: 0.189 AC: 7848 AN: 41524

American (AMR) AF: 0.396 AC: 6063 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2042 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2494 AN: 5170

South Asian (SAS) AF: 0.451 AC: 2178 AN: 4824

European-Finnish (FIN) AF: 0.551 AC: 5831 AN: 10580

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.564 AC: 38335 AN: 67980

Other (OTH) AF: 0.424 AC: 896 AN: 2114

Alfa AF: 0.523 Hom.: 79937

Bravo AF: 0.414

Asia WGS AF: 0.424 AC: 1479 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13219; hg19: chr12-1901434;