12-1879852-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_172364.5(CACNA2D4):c.1515A>G(p.Thr505Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,600,736 control chromosomes in the GnomAD database, including 20,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5998 hom., cov: 33)

Exomes 𝑓: 0.12 ( 14035 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.108

Publications

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

CACNA2D4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_172364.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-1879852-T-C is Benign according to our data. Variant chr12-1879852-T-C is described in ClinVar as Benign. ClinVar VariationId is 262809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.108 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 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.1515A>G	p.Thr505Thr	synonymous	Exon 14 of 38	NP_758952.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.1515A>G	p.Thr505Thr	synonymous	Exon 14 of 38	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5	TSL:5	c.1515A>G	p.Thr505Thr	synonymous	Exon 14 of 37	ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5	TSL:5	c.1515A>G	p.Thr505Thr	synonymous	Exon 14 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

33035

AN:

151996

Hom.:

5967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0348

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.128

AC:

29090

AN:

226974

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.502

Gnomad AMR exome

AF:

0.0671

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.0332

Gnomad FIN exome

AF:

0.0922

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.122

AC:

177390

AN:

1448620

Hom.:

14035

Cov.:

AF XY:

0.122

AC XY:

88086

AN XY:

719096

show subpopulations

African (AFR)

AF:

0.510

AC:

16902

AN:

33170

American (AMR)

AF:

0.0708

AC:

3044

AN:

43002

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3275

AN:

25842

East Asian (EAS)

AF:

0.0561

AC:

2206

AN:

39294

South Asian (SAS)

AF:

0.167

AC:

13930

AN:

83462

European-Finnish (FIN)

AF:

0.0924

AC:

4861

AN:

52580

Middle Eastern (MID)

AF:

0.132

AC:

757

AN:

5750

European-Non Finnish (NFE)

AF:

0.112

AC:

124181

AN:

1105584

Other (OTH)

AF:

0.137

AC:

8234

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

7076

14152

21228

28304

35380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4672

9344

14016

18688

23360

<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:

0.218

AC:

33115

AN:

152116

Hom.:

5998

Cov.:

AF XY:

0.212

AC XY:

15766

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.500

AC:

20748

AN:

41460

American (AMR)

AF:

0.112

AC:

1713

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

448

AN:

3468

East Asian (EAS)

AF:

0.0347

AC:

179

AN:

5162

South Asian (SAS)

AF:

0.170

AC:

821

AN:

4830

European-Finnish (FIN)

AF:

0.0850

AC:

902

AN:

10608

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7850

AN:

67982

Other (OTH)

AF:

0.171

AC:

360

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1113

2226

3340

4453

5566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.168

Hom.:

1537

Bravo

AF:

0.228

Asia WGS

AF:

0.166

AC:

577

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Retinal cone dystrophy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.4

(source)

DANN

Benign

0.28

PhyloP100

-0.11

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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