rs758160

Variant names:

• chr12-1874616-C-T
• rs758160
• NM_172364.5:c.1866G>A

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.1866G>A​(p.Pro622Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,610,304 control chromosomes in the GnomAD database, including 8,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (995 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7727 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.73
• Publications: 12 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):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinal cone dystrophy 4

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.69).
• BP6: Variant 12-1874616-C-T is Benign according to our data. Variant chr12-1874616-C-T is described in ClinVar as Benign. ClinVar VariationId is 262811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.1866G>A	p.Pro622Pro	synonymous	Exon 18 of 38	NP_758952.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.1866G>A	p.Pro622Pro	synonymous	Exon 18 of 38	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.1866G>A	p.Pro622Pro	synonymous	Exon 18 of 37	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.1791G>A	p.Pro597Pro	synonymous	Exon 17 of 37	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16012 AN: 152094 Hom.: 986 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0880

GnomAD2 exomes AF: 0.0935 AC: 23288 AN: 249116 AF XY: 0.0964

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0330

Gnomad FIN exome AF: 0.0831

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0965

GnomAD4 exome AF: 0.0995 AC: 145090 AN: 1458092 Hom.: 7727 Cov.: 29 AF XY: 0.100 AC XY: 72804 AN XY: 725546

African (AFR) AF: 0.143 AC: 4765 AN: 33384

American (AMR) AF: 0.0462 AC: 2067 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2770 AN: 26046

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

South Asian (SAS) AF: 0.127 AC: 10981 AN: 86164

European-Finnish (FIN) AF: 0.0834 AC: 4452 AN: 53400

Middle Eastern (MID) AF: 0.103 AC: 596 AN: 5766

European-Non Finnish (NFE) AF: 0.101 AC: 111661 AN: 1108670

Other (OTH) AF: 0.102 AC: 6133 AN: 60248

GnomAD4 genome AF: 0.105 AC: 16054 AN: 152212 Hom.: 995 Cov.: 32 AF XY: 0.102 AC XY: 7587 AN XY: 74422

African (AFR) AF: 0.141 AC: 5869 AN: 41516

American (AMR) AF: 0.0642 AC: 982 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3466

East Asian (EAS) AF: 0.0303 AC: 157 AN: 5182

South Asian (SAS) AF: 0.124 AC: 600 AN: 4826

European-Finnish (FIN) AF: 0.0745 AC: 790 AN: 10602

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

European-Non Finnish (NFE) AF: 0.103 AC: 7017 AN: 68006

Other (OTH) AF: 0.0908 AC: 192 AN: 2114

Alfa AF: 0.101 Hom.: 1364

Bravo AF: 0.103

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0981

EpiControl AF: 0.101

ClinVar

ClinVar submissions as Germline

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	-0.69
CADD	Benign	0.95
DANN	Benign	0.54
PhyloP100		-5.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs758160; hg19: chr12-1983782; COSMIC: COSV54947136;