chr12-1874616-C-T

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	c.1866G>A	p.Pro622Pro	synonymous_variant	Exon 18 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5	c.1791G>A	p.Pro597Pro	synonymous_variant	Exon 17 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5	c.1674G>A	p.Pro558Pro	synonymous_variant	Exon 18 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5	c.1674G>A	p.Pro558Pro	synonymous_variant	Exon 18 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6	n.*112G>A		non_coding_transcript_exon_variant	Exon 18 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6	n.*112G>A		3_prime_UTR_variant	Exon 18 of 37	1		ENSP00000403371.2

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

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 12, 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	-0.69
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;