rs62621429

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172364.5(CACNA2D4):c.2746G>A(p.Asp916Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0265 in 1,587,446 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 43 hom., cov: 32)

Exomes 𝑓: 0.027 ( 683 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.30

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinal cone dystrophy 4
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA2D4 links:

ENSG00000287698 (HGNC:):

ENSG00000287698 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010107875).

BP6

Variant 12-1801620-C-T is Benign according to our data. Variant chr12-1801620-C-T is described in ClinVar as Benign. ClinVar VariationId is 262816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3258/152298) while in subpopulation NFE AF = 0.0303 (2059/68022). AF 95% confidence interval is 0.0292. There are 43 homozygotes in GnomAd4. There are 1583 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.2746G>A	p.Asp916Asn	missense	Exon 30 of 38	NP_758952.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.2746G>A	p.Asp916Asn	missense	Exon 30 of 38	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	TSL:5	c.2746G>A	p.Asp916Asn	missense	Exon 30 of 37	ENSP00000465060.1
CACNA2D4	ENST00000587995.5	TSL:5	c.2671G>A	p.Asp891Asn	missense	Exon 29 of 37	ENSP00000465372.1

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3260

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0602

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0277

GnomAD2 exomes

AF:

0.0225

AC:

4709

AN:

208914

AF XY:

0.0232

show subpopulations

Gnomad AFR exome

AF:

0.00501

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0551

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.0299

Gnomad OTH exome

AF:

0.0282

GnomAD4 exome

AF:

0.0271

AC:

38839

AN:

1435148

Hom.:

683

Cov.:

AF XY:

0.0267

AC XY:

18967

AN XY:

711402

show subpopulations

African (AFR)

AF:

0.00463

AC:

152

AN:

32840

American (AMR)

AF:

0.0169

AC:

695

AN:

41142

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

1445

AN:

25588

East Asian (EAS)

AF:

0.0000521

AC:

AN:

38380

South Asian (SAS)

AF:

0.0147

AC:

1208

AN:

82046

European-Finnish (FIN)

AF:

0.0203

AC:

1051

AN:

51650

Middle Eastern (MID)

AF:

0.0350

AC:

201

AN:

5740

European-Non Finnish (NFE)

AF:

0.0295

AC:

32355

AN:

1098406

Other (OTH)

AF:

0.0291

AC:

1730

AN:

59356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1596

3192

4788

6384

7980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1196

2392

3588

4784

5980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0214

AC:

3258

AN:

152298

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

1583

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00558

AC:

232

AN:

41566

American (AMR)

AF:

0.0228

AC:

349

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0602

AC:

209

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.0141

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0225

AC:

239

AN:

10606

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0303

AC:

2059

AN:

68022

Other (OTH)

AF:

0.0279

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

175

350

526

701

876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0273

Hom.:

186

Bravo

AF:

0.0203

TwinsUK

AF:

0.0302

AC:

112

ALSPAC

AF:

0.0314

AC:

121

ESP6500AA

AF:

0.00517

AC:

ESP6500EA

AF:

0.0265

AC:

221

ExAC

AF:

0.0189

AC:

2280

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal cone dystrophy 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.4

PhyloP100

5.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.45

Sift

Benign

0.49

Sift4G

Uncertain

0.036

Polyphen

0.96

Vest4

0.62

MPC

0.16

ClinPred

0.033

GERP RS

4.7

Varity_R

0.12

gMVP

0.88

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over