rs11836202

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-1846620-G-A
• chr12-1846620-G-C

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2316C>T	p.Phe772Phe	synonymous_variant	Exon 24 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2316C>T	p.Phe772Phe	synonymous_variant	Exon 24 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2316C>T	p.Phe772Phe	synonymous_variant	Exon 24 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.2241C>T	p.Phe747Phe	synonymous_variant	Exon 23 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.2124C>T	p.Phe708Phe	synonymous_variant	Exon 24 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.2124C>T	p.Phe708Phe	synonymous_variant	Exon 24 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*562C>T		non_coding_transcript_exon_variant	Exon 24 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5	n.156C>T		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000444595.6	n.*562C>T		3_prime_UTR_variant	Exon 24 of 37	1		ENSP00000403371.2

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal cone dystrophy 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;