rs3815325

Variant names:

• chr12-1795925-G-A
• rs3815325
• NM_172364.5:c.3114-145C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172364.5(CACNA2D4):​c.3114-145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 652,156 control chromosomes in the GnomAD database, including 20,219 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6345 hom., cov: 32)
  • Exomes 𝑓: 0.23 (13874 hom.)
• Consequence: CACNA2D4 NM_172364.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.781
• Publications: 6 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: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.391 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.3114-145C>T		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.3114-145C>T		intron	N/A	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.3114-145C>T		intron	N/A	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.3039-145C>T		intron	N/A	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41717 AN: 152020 Hom.: 6334 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.230 AC: 114783 AN: 500018 Hom.: 13874 Cov.: 4 AF XY: 0.232 AC XY: 62119 AN XY: 268224

African (AFR) AF: 0.397 AC: 5515 AN: 13886

American (AMR) AF: 0.261 AC: 6791 AN: 26056

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 3785 AN: 15438

East Asian (EAS) AF: 0.208 AC: 6752 AN: 32496

South Asian (SAS) AF: 0.275 AC: 15084 AN: 54926

European-Finnish (FIN) AF: 0.151 AC: 5014 AN: 33258

Middle Eastern (MID) AF: 0.251 AC: 704 AN: 2810

European-Non Finnish (NFE) AF: 0.219 AC: 64282 AN: 292986

Other (OTH) AF: 0.243 AC: 6856 AN: 28162

GnomAD4 genome AF: 0.275 AC: 41767 AN: 152138 Hom.: 6345 Cov.: 32 AF XY: 0.271 AC XY: 20183 AN XY: 74386

African (AFR) AF: 0.396 AC: 16434 AN: 41488

American (AMR) AF: 0.295 AC: 4512 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1281 AN: 5176

South Asian (SAS) AF: 0.288 AC: 1389 AN: 4818

European-Finnish (FIN) AF: 0.143 AC: 1518 AN: 10606

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.218 AC: 14837 AN: 67966

Other (OTH) AF: 0.277 AC: 586 AN: 2114

Alfa AF: 0.252 Hom.: 1184

Bravo AF: 0.289

Asia WGS AF: 0.286 AC: 994 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.37
PhyloP100		-0.78
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3815325;

hg19: chr12-1905091;

COSMIC: COSV54957961;

COSMIC: COSV54957961;