chr12-1793763-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):

CACNA2D4-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinal cone dystrophy 4
Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D4	NM_172364.5	MANE Select	c.3310-4G>A		splice_region intron	N/A	NP_758952.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.3310-4G>A	splice_region intron	N/A	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000587995.5	TSL:5	c.3235-4G>A	splice_region intron	N/A	ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000588077.5	TSL:5	c.3118-4G>A	splice_region intron	N/A	ENSP00000468530.1	Q7Z3S7-4

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Retinal cone dystrophy 4 (1)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over