rs2286372

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_172364.5(CACNA2D4):c.2035C>T(p.Leu679=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.137

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
CACNA2D4	NM_172364.5 linkuse as main transcript	c.2035C>T	p.Leu679=	synonymous_variant	21/38	ENST00000382722.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.2035C>T	p.Leu679=	synonymous_variant	21/38	1	NM_172364.5	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.0699

AC:

10634

AN:

152192

Hom.:

852

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0975

AC:

24305

AN:

249224

Hom.:

2793

AF XY:

0.0956

AC XY:

12922

AN XY:

135208

show subpopulations

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 SAS exome

AF:

0.187

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.:

AF XY:

0.0490

AC XY:

35630

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.0457

Gnomad4 EAS exome

AF:

0.449

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.0402

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0591

GnomAD4 genome

AF:

0.0698

AC:

10629

AN:

152310

Hom.:

849

Cov.:

AF XY:

0.0774

AC XY:

5762

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0957

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.0438

Gnomad4 EAS

AF:

0.404

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.0413

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.0700

Alfa

AF:

0.0306

Hom.:

228

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.54

CADD

Benign

9.4

DANN

Benign

0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over