12-1793763-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172364.5(CACNA2D4):c.3310-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,611,862 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 113 hom., cov: 32)

Exomes 𝑓: 0.011 ( 429 hom. )

Consequence

CACNA2D4
NM_172364.5 splice_region, intron

Scores

Splicing: ADA: 0.00005592

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.04

Publications

5 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:

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=-0.86).

BP6

Variant 12-1793763-C-T is Benign according to our data. Variant chr12-1793763-C-T is described in ClinVar as Benign. ClinVar VariationId is 262818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.3310-4G>A		splice_region_variant, intron_variant	Intron 37 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.3310-4G>A	splice_region_variant, intron_variant	Intron 37 of 37	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000587995.5 link	c.3235-4G>A	splice_region_variant, intron_variant	Intron 36 of 36	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000588077.5 link	c.3118-4G>A	splice_region_variant, intron_variant	Intron 37 of 37	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.748-4G>A	splice_region_variant, intron_variant	Intron 11 of 11	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.745-4G>A	splice_region_variant, intron_variant	Intron 11 of 11	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.700-4G>A	splice_region_variant, intron_variant	Intron 10 of 10	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*1494-4G>A	splice_region_variant, intron_variant	Intron 36 of 36	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*503-4G>A	splice_region_variant, intron_variant	Intron 14 of 14	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*503-4G>A	splice_region_variant, intron_variant	Intron 9 of 9	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*503-4G>A	splice_region_variant, intron_variant	Intron 10 of 10	5		ENSP00000467333.1	K7EIY9

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4114

AN:

152194

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0774

Gnomad SAS

AF:

0.0436

Gnomad FIN

AF:

0.0739

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0262

AC:

6397

AN:

244554

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.0536

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.000604

Gnomad EAS exome

AF:

0.0744

Gnomad FIN exome

AF:

0.0754

Gnomad NFE exome

AF:

0.00451

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0114

AC:

16575

AN:

1459550

Hom.:

429

Cov.:

AF XY:

0.0120

AC XY:

8732

AN XY:

726148

show subpopulations

African (AFR)

AF:

0.0538

AC:

1797

AN:

33428

American (AMR)

AF:

0.0230

AC:

1030

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.000498

AC:

AN:

26086

East Asian (EAS)

AF:

0.0675

AC:

2678

AN:

39682

South Asian (SAS)

AF:

0.0407

AC:

3507

AN:

86186

European-Finnish (FIN)

AF:

0.0704

AC:

3709

AN:

52700

Middle Eastern (MID)

AF:

0.00739

AC:

AN:

5414

European-Non Finnish (NFE)

AF:

0.00260

AC:

2885

AN:

1111082

Other (OTH)

AF:

0.0152

AC:

916

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

876

1752

2629

3505

4381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.0272

AC:

4136

AN:

152312

Hom.:

113

Cov.:

AF XY:

0.0303

AC XY:

2255

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0519

AC:

2158

AN:

41566

American (AMR)

AF:

0.0177

AC:

271

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.0777

AC:

403

AN:

5184

South Asian (SAS)

AF:

0.0433

AC:

209

AN:

4830

European-Finnish (FIN)

AF:

0.0739

AC:

784

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00384

AC:

261

AN:

68026

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0132

Hom.:

Bravo

AF:

0.0246

Asia WGS

AF:

0.0890

AC:

307

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Retinal cone dystrophy 4

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.14

(source)

DANN

Benign

0.64

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000056

dbscSNV1_RF

Benign

0.0

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