NM_172364.5:c.2793-15G>A

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.2793-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,612,218 control chromosomes in the GnomAD database, including 742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 43 hom., cov: 33)

Exomes 𝑓: 0.027 ( 699 hom. )

Consequence

CACNA2D4
NM_172364.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0980

Publications

2 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 (BayesDel_noAF=-0.85).

BP6

Variant 12-1801133-C-T is Benign according to our data. Variant chr12-1801133-C-T is described in ClinVar as Benign. ClinVar VariationId is 262817.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 = 0.0221 (3362/152242) while in subpopulation NFE AF = 0.0303 (2063/67994). AF 95% confidence interval is 0.0293. There are 43 homozygotes in GnomAd4. There are 1629 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2793-15G>A		intron_variant	Intron 30 of 37	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2793-15G>A	intron_variant	Intron 30 of 37	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2793-15G>A	intron_variant	Intron 30 of 36	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2718-15G>A	intron_variant	Intron 29 of 36	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2601-15G>A	intron_variant	Intron 30 of 36	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2601-15G>A	intron_variant	Intron 30 of 37	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.237-15G>A	intron_variant	Intron 4 of 11	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.228-15G>A	intron_variant	Intron 4 of 11	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.183-15G>A	intron_variant	Intron 3 of 10	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*977-15G>A	intron_variant	Intron 29 of 36	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.562-15G>A	intron_variant	Intron 7 of 14	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.112-15G>A	intron_variant	Intron 2 of 9	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.157-15G>A	intron_variant	Intron 3 of 10	5		ENSP00000467333.1	K7EIY9

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3353

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00801

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.0603

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0227

AC:

5646

AN:

248790

AF XY:

0.0234

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.0161

Gnomad ASJ exome

AF:

0.0555

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.0300

Gnomad OTH exome

AF:

0.0283

GnomAD4 exome

AF:

0.0269

AC:

39319

AN:

1459976

Hom.:

699

Cov.:

AF XY:

0.0266

AC XY:

19314

AN XY:

726408

show subpopulations

African (AFR)

AF:

0.00810

AC:

271

AN:

33458

American (AMR)

AF:

0.0168

AC:

750

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

1476

AN:

26120

East Asian (EAS)

AF:

0.000101

AC:

AN:

39694

South Asian (SAS)

AF:

0.0150

AC:

1291

AN:

86226

European-Finnish (FIN)

AF:

0.0201

AC:

1073

AN:

53378

Middle Eastern (MID)

AF:

0.0339

AC:

195

AN:

5758

European-Non Finnish (NFE)

AF:

0.0293

AC:

32477

AN:

1110316

Other (OTH)

AF:

0.0295

AC:

1782

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

1857

3713

5570

7426

9283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1186

2372

3558

4744

5930

<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:

0.0221

AC:

3362

AN:

152242

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1629

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00825

AC:

343

AN:

41556

American (AMR)

AF:

0.0223

AC:

341

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0603

AC:

209

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0141

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0221

AC:

235

AN:

10610

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0303

AC:

2063

AN:

67994

Other (OTH)

AF:

0.0284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

174

347

521

694

868

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:

0.0251

Hom.:

Bravo

AF:

0.0210

Asia WGS

AF:

0.0100

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

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.54

(source)

DANN

Benign

0.53

PhyloP100

0.098

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over