rs7966806

Variant names:

• chr12-1879001-T-C
• rs7966806
• NM_172364.5:c.1599A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_172364.5(CACNA2D4):​c.1599A>G​(p.Ser533Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,812 control chromosomes in the GnomAD database, including 12,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2659 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9387 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.24
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-1879001-T-C is Benign according to our data. Variant chr12-1879001-T-C is described in ClinVar as Benign. ClinVar VariationId is 262810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 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.1599A>G	p.Ser533Ser	synonymous	Exon 15 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.1599A>G	p.Ser533Ser	synonymous	Exon 15 of 38	ENSP00000372169.4	Q7Z3S7-1
	CACNA2D4	ENST00000586184.5	TSL:5	c.1599A>G	p.Ser533Ser	synonymous	Exon 15 of 37	ENSP00000465060.1	Q7Z3S7-5
	CACNA2D4	ENST00000587995.5	TSL:5	c.1599A>G	p.Ser533Ser	synonymous	Exon 15 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23764 AN: 151978 Hom.: 2643 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0839

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.107 AC: 26590 AN: 248620 AF XY: 0.107

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0332

Gnomad FIN exome AF: 0.0892

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.106 AC: 155005 AN: 1460716 Hom.: 9387 Cov.: 31 AF XY: 0.106 AC XY: 77120 AN XY: 726620

African (AFR) AF: 0.315 AC: 10526 AN: 33428

American (AMR) AF: 0.0560 AC: 2501 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2869 AN: 26116

East Asian (EAS) AF: 0.0419 AC: 1665 AN: 39696

South Asian (SAS) AF: 0.128 AC: 11022 AN: 86122

European-Finnish (FIN) AF: 0.0890 AC: 4745 AN: 53302

Middle Eastern (MID) AF: 0.109 AC: 629 AN: 5766

European-Non Finnish (NFE) AF: 0.103 AC: 114238 AN: 1111266

Other (OTH) AF: 0.113 AC: 6810 AN: 60334

GnomAD4 genome AF: 0.157 AC: 23828 AN: 152096 Hom.: 2659 Cov.: 32 AF XY: 0.152 AC XY: 11342 AN XY: 74374

African (AFR) AF: 0.314 AC: 13031 AN: 41442

American (AMR) AF: 0.0836 AC: 1279 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3464

East Asian (EAS) AF: 0.0304 AC: 157 AN: 5170

South Asian (SAS) AF: 0.126 AC: 607 AN: 4822

European-Finnish (FIN) AF: 0.0814 AC: 863 AN: 10604

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7177 AN: 67980

Other (OTH) AF: 0.118 AC: 249 AN: 2108

Alfa AF: 0.125 Hom.: 1070

Bravo AF: 0.159

Asia WGS AF: 0.124 AC: 428 AN: 3478

EpiCase AF: 0.0982

EpiControl AF: 0.103

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.51
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7966806; hg19: chr12-1988167; COSMIC: COSV54947144; COSMIC: COSV54947144;