12-1846620-G-A

Variant names:

• chr12-1846620-G-A
• rs11836202
• NM_172364.5:c.2316C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_172364.5(CACNA2D4):​c.2316C>T​(p.Phe772Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,601,608 control chromosomes in the GnomAD database, including 7,496 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (823 hom., cov: 33)
  • Exomes 𝑓: 0.045 (6673 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0530
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-1846620-G-A is Benign according to our data. Variant chr12-1846620-G-A is described in ClinVar as Benign. ClinVar VariationId is 262814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.382 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.2316C>T	p.Phe772Phe	synonymous	Exon 24 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.2316C>T	p.Phe772Phe	synonymous	Exon 24 of 38	ENSP00000372169.4
	CACNA2D4	ENST00000586184.5	TSL:5	c.2316C>T	p.Phe772Phe	synonymous	Exon 24 of 37	ENSP00000465060.1
	CACNA2D4	ENST00000587995.5	TSL:5	c.2241C>T	p.Phe747Phe	synonymous	Exon 23 of 37	ENSP00000465372.1

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9889 AN: 152082 Hom.: 819 Cov.: 33

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0642

GnomAD2 exomes AF: 0.0967 AC: 22439 AN: 231980 AF XY: 0.0964

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.411

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0451 AC: 65332 AN: 1449408 Hom.: 6673 Cov.: 32 AF XY: 0.0493 AC XY: 35493 AN XY: 720278

African (AFR) AF: 0.0897 AC: 2987 AN: 33310

American (AMR) AF: 0.152 AC: 6615 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 867 AN: 25916

East Asian (EAS) AF: 0.420 AC: 16495 AN: 39260

South Asian (SAS) AF: 0.214 AC: 17980 AN: 84208

European-Finnish (FIN) AF: 0.0204 AC: 990 AN: 48550

Middle Eastern (MID) AF: 0.0537 AC: 309 AN: 5756

European-Non Finnish (NFE) AF: 0.0140 AC: 15535 AN: 1108700

Other (OTH) AF: 0.0591 AC: 3554 AN: 60110

GnomAD4 genome AF: 0.0650 AC: 9897 AN: 152200 Hom.: 823 Cov.: 33 AF XY: 0.0719 AC XY: 5349 AN XY: 74412

African (AFR) AF: 0.0831 AC: 3451 AN: 41508

American (AMR) AF: 0.113 AC: 1728 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 123 AN: 3468

East Asian (EAS) AF: 0.396 AC: 2040 AN: 5146

South Asian (SAS) AF: 0.224 AC: 1082 AN: 4822

European-Finnish (FIN) AF: 0.0200 AC: 213 AN: 10630

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1099 AN: 68014

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0278 Hom.: 112

Bravo AF: 0.0715

Asia WGS AF: 0.309 AC: 1072 AN: 3478

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	-0.37
CADD	Benign	7.2
DANN	Benign	0.74
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11836202; hg19: chr12-1955786; COSMIC: COSV54949371;