12-1914926-T-C

Position:

• chr12-1914926-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000382722.10(CACNA2D4):​c.237A>G​(p.Leu79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,610,796 control chromosomes in the GnomAD database, including 7,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (555 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6952 hom.)
• Consequence: CACNA2D4 ENST00000382722.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.462

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-1914926-T-C is Benign according to our data. Variant chr12-1914926-T-C is described in ClinVar as [Benign]. Clinvar id is 262815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.462 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.237A>G	p.Leu79=	synonymous_variant	2/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.237A>G	p.Leu79=	synonymous_variant	2/38	1	NM_172364.5	ENSP00000372169	P2

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10529 AN: 151974 Hom.: 555 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0794

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0676

GnomAD3 exomes AF: 0.0782 AC: 19482 AN: 249214 Hom.: 933 AF XY: 0.0814 AC XY: 11010 AN XY: 135198

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.0884

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0899

GnomAD4 exome AF: 0.0930 AC: 135666 AN: 1458704 Hom.: 6952 Cov.: 30 AF XY: 0.0932 AC XY: 67643 AN XY: 725842

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.0412

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0854

Gnomad4 FIN exome AF: 0.0882

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.0894

GnomAD4 genome AF: 0.0692 AC: 10527 AN: 152092 Hom.: 555 Cov.: 32 AF XY: 0.0666 AC XY: 4952 AN XY: 74334

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.0800

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0664

Alfa AF: 0.0923 Hom.: 393

Bravo AF: 0.0620

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.0986

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.6
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs73038195; hg19: chr12-2024092;