rs33912216

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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.38

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=-0.87).

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	Protein	UniProt
CACNA2D4	NM_172364.5 linkuse as main transcript	c.3330C>T	p.Gly1110=	synonymous_variant	38/38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.3330C>T	p.Gly1110=	synonymous_variant	38/38	1	NM_172364.5	ENSP00000372169	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16322

AN:

152152

Hom.:

992

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0956

AC XY:

69486

AN XY:

726606

show subpopulations

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.:

AF XY:

0.109

AC XY:

8149

AN XY:

74454

show subpopulations

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	- -

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	- -

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

-0.87

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

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