rs33912216

chr12-1793739-G-Achr12-1793739-G-C

Variant summary

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

The NM_172364.5(CACNA2D4):c.3330C>T(p.Gly1110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,612,800 control chromosomes in the GnomAD database, including 8,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (991 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7593 hom.)
• Consequence: CACNA2D4 NM_172364.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.38

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=-0.87).
• BP6: Variant 12-1793739-G-A is Benign according to our data. Variant chr12-1793739-G-A is described in ClinVar as [Benign]. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA2D4	NM_172364.5	c.3330C>T	p.Gly1110=	synonymous_variant	38/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10	c.3330C>T	p.Gly1110=	synonymous_variant	38/38	1	NM_172364.5	P2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16322 AN: 152152 Hom.: 992 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.114 AC: 28140 AN: 245934 Hom.: 2050 AF XY: 0.111 AC XY: 14855 AN XY: 134104

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.0767

Gnomad EAS exome AF: 0.0537

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0957 AC: 139733 AN: 1460530 Hom.: 7593 Cov.: 32 AF XY: 0.0956 AC XY: 69486 AN XY: 726606

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.0757

Gnomad4 EAS exome AF: 0.0528

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0880

Gnomad4 OTH exome AF: 0.0970

GnomAD4 genome AF: 0.107 AC: 16334 AN: 152270 Hom.: 991 Cov.: 33 AF XY: 0.109 AC XY: 8149 AN XY: 74454

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.0638

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0851

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0999 Hom.: 620

Bravo AF: 0.115

Asia WGS AF: 0.102 AC: 356 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0893

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2014	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.030
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs33912216; hg19: chr12-1902905; COSMIC: COSV54959742; COSMIC: COSV54959742;