rs2286372

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2035C>T(p.Leu679Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,613,974 control chromosomes in the GnomAD database, including 7,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L679L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.070 ( 849 hom., cov: 33)

Exomes 𝑓: 0.046 ( 6929 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.137

Publications

15 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 12-1856203-G-A is Benign according to our data. Variant chr12-1856203-G-A is described in ClinVar as Benign. ClinVar VariationId is 262812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.137 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.39 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.2035C>T	p.Leu679Leu	synonymous	Exon 21 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.2035C>T	p.Leu679Leu	synonymous	Exon 21 of 38	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5	TSL:5	c.2035C>T	p.Leu679Leu	synonymous	Exon 21 of 37	ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5	TSL:5	c.1960C>T	p.Leu654Leu	synonymous	Exon 20 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes

AF:

0.0699

AC:

10634

AN:

152192

Hom.:

852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0959

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.404

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.0413

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0688

GnomAD2 exomes

AF:

0.0975

AC:

24305

AN:

249224

AF XY:

0.0956

show subpopulations

Gnomad AFR exome

AF:

0.0964

Gnomad AMR exome

AF:

0.169

Gnomad ASJ exome

AF:

0.0442

Gnomad EAS exome

AF:

0.416

Gnomad FIN exome

AF:

0.0393

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0714

GnomAD4 exome

AF:

0.0456

AC:

66646

AN:

1461664

Hom.:

6929

Cov.:

AF XY:

0.0490

AC XY:

35630

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.101

AC:

3394

AN:

33478

American (AMR)

AF:

0.162

AC:

7243

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0457

AC:

1193

AN:

26126

East Asian (EAS)

AF:

0.449

AC:

17811

AN:

39698

South Asian (SAS)

AF:

0.185

AC:

15936

AN:

86250

European-Finnish (FIN)

AF:

0.0402

AC:

2145

AN:

53394

Middle Eastern (MID)

AF:

0.0642

AC:

370

AN:

5766

European-Non Finnish (NFE)

AF:

0.0135

AC:

14989

AN:

1111862

Other (OTH)

AF:

0.0591

AC:

3565

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3478

6955

10433

13910

17388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

966

1932

2898

3864

4830

<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:

0.0698

AC:

10629

AN:

152310

Hom.:

849

Cov.:

AF XY:

0.0774

AC XY:

5762

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0957

AC:

3979

AN:

41568

American (AMR)

AF:

0.117

AC:

1797

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0438

AC:

152

AN:

3470

East Asian (EAS)

AF:

0.404

AC:

2092

AN:

5176

South Asian (SAS)

AF:

0.188

AC:

909

AN:

4824

European-Finnish (FIN)

AF:

0.0413

AC:

439

AN:

10624

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1098

AN:

68024

Other (OTH)

AF:

0.0700

AC:

148

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

490

981

1471

1962

2452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0344

Hom.:

332

Bravo

AF:

0.0761

Asia WGS

AF:

0.270

AC:

937

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0205

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

-0.54

CADD

Benign

9.4

(source)

DANN

Benign

0.46

PhyloP100

0.14

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Computational scores

Splicing

Publications

Other links and lift over