rs2286372

Variant names:

• chr12-1856203-G-A
• rs2286372
• NM_172364.5:c.2035C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-1856203-G-A
• chr12-1856203-G-C
• chr12-1856203-G-T

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.2035C>T​(p.Leu679Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,613,974 control chromosomes in the GnomAD database, including 7,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L679L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.070 (849 hom., cov: 33)
  • Exomes 𝑓: 0.046 (6929 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.137
• Publications: 15 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=-0.54).
• BP6: Variant 12-1856203-G-A is Benign according to our data. Variant chr12-1856203-G-A is described in ClinVar as Benign. ClinVar VariationId is 262812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.2035C>T	p.Leu679Leu	synonymous_variant	Exon 21 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2035C>T	p.Leu679Leu	synonymous_variant	Exon 21 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.2035C>T	p.Leu679Leu	synonymous_variant	Exon 21 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1960C>T	p.Leu654Leu	synonymous_variant	Exon 20 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1843C>T	p.Leu615Leu	synonymous_variant	Exon 21 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1843C>T	p.Leu615Leu	synonymous_variant	Exon 21 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*281C>T		non_coding_transcript_exon_variant	Exon 21 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*281C>T		3_prime_UTR_variant	Exon 21 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10634 AN: 152192 Hom.: 852 Cov.: 33

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0688

GnomAD2 exomes AF: 0.0975 AC: 24305 AN: 249224 AF XY: 0.0956

Gnomad AFR exome AF: 0.0964

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0714

GnomAD4 exome AF: 0.0456 AC: 66646 AN: 1461664 Hom.: 6929 Cov.: 33 AF XY: 0.0490 AC XY: 35630 AN XY: 727116

African (AFR) AF: 0.101 AC: 3394 AN: 33478

American (AMR) AF: 0.162 AC: 7243 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 1193 AN: 26126

East Asian (EAS) AF: 0.449 AC: 17811 AN: 39698

South Asian (SAS) AF: 0.185 AC: 15936 AN: 86250

European-Finnish (FIN) AF: 0.0402 AC: 2145 AN: 53394

Middle Eastern (MID) AF: 0.0642 AC: 370 AN: 5766

European-Non Finnish (NFE) AF: 0.0135 AC: 14989 AN: 1111862

Other (OTH) AF: 0.0591 AC: 3565 AN: 60366

GnomAD4 genome AF: 0.0698 AC: 10629 AN: 152310 Hom.: 849 Cov.: 33 AF XY: 0.0774 AC XY: 5762 AN XY: 74488

African (AFR) AF: 0.0957 AC: 3979 AN: 41568

American (AMR) AF: 0.117 AC: 1797 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2092 AN: 5176

South Asian (SAS) AF: 0.188 AC: 909 AN: 4824

European-Finnish (FIN) AF: 0.0413 AC: 439 AN: 10624

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1098 AN: 68024

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0344 Hom.: 332

Bravo AF: 0.0761

Asia WGS AF: 0.270 AC: 937 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.54
CADD	Benign	9.4
DANN	Benign	0.46
PhyloP100		0.14
Mutation Taster		=98/2	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: rs2286372; hg19: chr12-1965369; COSMIC: COSV54947103; COSMIC: COSV54947103;