rs62621429

Variant names:

• chr12-1801620-C-T
• rs62621429
• NM_172364.5:c.2746G>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.2746G>A​(p.Asp916Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0265 in 1,587,446 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 32)
  • Exomes 𝑓: 0.027 (683 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.30
• Publications: 8 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 (MetaRNN=0.010107875).
• BP6: Variant 12-1801620-C-T is Benign according to our data. Variant chr12-1801620-C-T is described in ClinVar as Benign. ClinVar VariationId is 262816.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 = 0.0214 (3258/152298) while in subpopulation NFE AF = 0.0303 (2059/68022). AF 95% confidence interval is 0.0292. There are 43 homozygotes in GnomAd4. There are 1583 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.2746G>A	p.Asp916Asn	missense	Exon 30 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.2746G>A	p.Asp916Asn	missense	Exon 30 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.2746G>A	p.Asp916Asn	missense	Exon 30 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.2671G>A	p.Asp891Asn	missense	Exon 29 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3260 AN: 152180 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0225 AC: 4709 AN: 208914 AF XY: 0.0232

Gnomad AFR exome AF: 0.00501

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0271 AC: 38839 AN: 1435148 Hom.: 683 Cov.: 30 AF XY: 0.0267 AC XY: 18967 AN XY: 711402

African (AFR) AF: 0.00463 AC: 152 AN: 32840

American (AMR) AF: 0.0169 AC: 695 AN: 41142

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1445 AN: 25588

East Asian (EAS) AF: 0.0000521 AC: 2 AN: 38380

South Asian (SAS) AF: 0.0147 AC: 1208 AN: 82046

European-Finnish (FIN) AF: 0.0203 AC: 1051 AN: 51650

Middle Eastern (MID) AF: 0.0350 AC: 201 AN: 5740

European-Non Finnish (NFE) AF: 0.0295 AC: 32355 AN: 1098406

Other (OTH) AF: 0.0291 AC: 1730 AN: 59356

GnomAD4 genome AF: 0.0214 AC: 3258 AN: 152298 Hom.: 43 Cov.: 32 AF XY: 0.0213 AC XY: 1583 AN XY: 74472

African (AFR) AF: 0.00558 AC: 232 AN: 41566

American (AMR) AF: 0.0228 AC: 349 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4826

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0303 AC: 2059 AN: 68022

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0273 Hom.: 186

Bravo AF: 0.0203

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.00517 AC: 21

ESP6500EA AF: 0.0265 AC: 221

ExAC AF: 0.0189 AC: 2280

Asia WGS AF: 0.00837 AC: 29 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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.49	T
Sift4G	Uncertain	0.036	D
Polyphen		0.96	D
Vest4		0.62
MPC		0.16
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.88
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62621429; hg19: chr12-1910786;