rs11836202

chr12-1846620-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_172364.5(CACNA2D4):c.2316C>T(p.Phe772=) 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:3
• Conservation: PhyloP100: -0.0530

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.2316C>T	p.Phe772=	synonymous_variant	24/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.2316C>T	p.Phe772=	synonymous_variant	24/38	1	NM_172364.5	P2

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

GnomAD3 exomes AF: 0.0967 AC: 22439 AN: 231980 Hom.: 2683 AF XY: 0.0964 AC XY: 12147 AN XY: 126036

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 SAS exome AF: 0.218

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

Gnomad4 AFR exome AF: 0.0897

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0591

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

Gnomad4 AFR AF: 0.0831

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0355

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0706

Alfa AF: 0.0286 Hom.: 64

Bravo AF: 0.0715

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Retinal cone dystrophy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	7.2
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs11836202; hg19: chr12-1955786; COSMIC: COSV54949371;