rs10735005

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172364.5(CACNA2D4):c.979A>G(p.Ile327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 1,612,314 control chromosomes in the GnomAD database, including 648,295 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64041 hom., cov: 30)

Exomes 𝑓: 0.89 ( 584254 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.20

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:

LOC124902858 (HGNC:):

LOC124902858 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9109855E-6).

BP6

Variant 12-1886237-T-C is Benign according to our data. Variant chr12-1886237-T-C is described in ClinVar as [Benign]. Clinvar id is 262820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1886237-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.979A>G	p.Ile327Val	missense_variant	8/38	ENST00000382722.10	NP_758952.4
LOC124902858	XR_007063158.1 linkuse as main transcript	n.295-19T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D4	ENST00000382722.10 linkuse as main transcript	c.979A>G	p.Ile327Val	missense_variant	8/38	1	NM_172364.5	ENSP00000372169	P2	Q7Z3S7-1

Frequencies

GnomAD3 genomes

AF:

0.916

AC:

139265

AN:

152006

Hom.:

63975

Cov.:

show subpopulations

Gnomad AFR

AF:

0.978

Gnomad AMI

AF:

0.834

Gnomad AMR

AF:

0.892

Gnomad ASJ

AF:

0.857

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.910

Gnomad FIN

AF:

0.894

Gnomad MID

AF:

0.844

Gnomad NFE

AF:

0.887

Gnomad OTH

AF:

0.889

GnomAD3 exomes

AF:

0.903

AC:

225118

AN:

249246

Hom.:

101899

AF XY:

0.901

AC XY:

121784

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.982

Gnomad AMR exome

AF:

0.890

Gnomad ASJ exome

AF:

0.845

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.912

Gnomad FIN exome

AF:

0.891

Gnomad NFE exome

AF:

0.888

Gnomad OTH exome

AF:

0.881

GnomAD4 exome

AF:

0.894

AC:

1305653

AN:

1460190

Hom.:

584254

Cov.:

AF XY:

0.894

AC XY:

649146

AN XY:

726462

show subpopulations

Gnomad4 AFR exome

AF:

0.984

Gnomad4 AMR exome

AF:

0.892

Gnomad4 ASJ exome

AF:

0.850

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.907

Gnomad4 FIN exome

AF:

0.886

Gnomad4 NFE exome

AF:

0.888

Gnomad4 OTH exome

AF:

0.900

GnomAD4 genome

AF:

0.916

AC:

139390

AN:

152124

Hom.:

64041

Cov.:

AF XY:

0.916

AC XY:

68131

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.978

Gnomad4 AMR

AF:

0.892

Gnomad4 ASJ

AF:

0.857

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.911

Gnomad4 FIN

AF:

0.894

Gnomad4 NFE

AF:

0.887

Gnomad4 OTH

AF:

0.891

Alfa

AF:

0.888

Hom.:

153626

Bravo

AF:

0.919

TwinsUK

AF:

0.894

AC:

3316

ALSPAC

AF:

0.887

AC:

3417

ESP6500AA

AF:

0.977

AC:

4072

ESP6500EA

AF:

0.886

AC:

7459

ExAC

AF:

0.906

AC:

109585

Asia WGS

AF:

0.961

AC:

3344

AN:

3478

EpiCase

AF:

0.876

EpiControl

AF:

0.874

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal cone dystrophy 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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: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

- -

Cone dystrophy 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.5

DANN

Benign

0.49

DEOGEN2

Benign

0.052

T;.;.;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.23

MetaRNN

Benign

0.0000019

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.0

N;.;.;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.44

N;.;.;.;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;.;.;.;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.054

MPC

0.11

ClinPred

0.0026

GERP RS

5.2

Varity_R

0.092

gMVP

0.26

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

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