12-1840773-C-T

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.2517G>A(p.Ala839Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,590 control chromosomes in the GnomAD database, including 10,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1798 hom., cov: 34)

Exomes 𝑓: 0.10 ( 8440 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.06

Publications

6 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 -21 ACMG points.

BP4

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

BP6

Variant 12-1840773-C-T is Benign according to our data. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1840773-C-T is described in CliVar as Benign. Clinvar id is 100607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2517G>A	p.Ala839Ala	synonymous_variant	Exon 26 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1
CACNA2D4	XM_011521041.3 link	c.2454G>A	p.Ala818Ala	synonymous_variant	Exon 25 of 36		XP_011519343.1
CACNA2D4	XM_047429897.1 link	c.2445G>A	p.Ala815Ala	synonymous_variant	Exon 25 of 36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2517G>A	p.Ala839Ala	synonymous_variant	Exon 26 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2517G>A	p.Ala839Ala	synonymous_variant	Exon 26 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2442G>A	p.Ala814Ala	synonymous_variant	Exon 25 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2325G>A	p.Ala775Ala	synonymous_variant	Exon 26 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2325G>A	p.Ala775Ala	synonymous_variant	Exon 26 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.*763G>A		non_coding_transcript_exon_variant	Exon 26 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.357G>A		non_coding_transcript_exon_variant	Exon 4 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000444595.6 link	n.*763G>A		3_prime_UTR_variant	Exon 26 of 37	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20652

AN:

152100

Hom.:

1794

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0875

Gnomad ASJ

AF:

0.0942

Gnomad EAS

AF:

0.0146

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.104

AC:

25861

AN:

249110

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0896

Gnomad ASJ exome

AF:

0.0916

Gnomad EAS exome

AF:

0.0141

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.103

AC:

149916

AN:

1461372

Hom.:

8440

Cov.:

AF XY:

0.102

AC XY:

74021

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.235

AC:

7880

AN:

33472

American (AMR)

AF:

0.0892

AC:

3987

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0946

AC:

2470

AN:

26120

East Asian (EAS)

AF:

0.0131

AC:

519

AN:

39700

South Asian (SAS)

AF:

0.103

AC:

8914

AN:

86256

European-Finnish (FIN)

AF:

0.107

AC:

5705

AN:

53280

Middle Eastern (MID)

AF:

0.0758

AC:

437

AN:

5768

European-Non Finnish (NFE)

AF:

0.102

AC:

113692

AN:

1111688

Other (OTH)

AF:

0.105

AC:

6312

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

6657

13314

19972

26629

33286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4178

8356

12534

16712

20890

<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:

0.136

AC:

20696

AN:

152218

Hom.:

1798

Cov.:

AF XY:

0.133

AC XY:

9889

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.238

AC:

9889

AN:

41500

American (AMR)

AF:

0.0873

AC:

1336

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0942

AC:

327

AN:

3470

East Asian (EAS)

AF:

0.0149

AC:

AN:

5184

South Asian (SAS)

AF:

0.104

AC:

501

AN:

4830

European-Finnish (FIN)

AF:

0.105

AC:

1109

AN:

10608

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7138

AN:

68008

Other (OTH)

AF:

0.110

AC:

233

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

895

1790

2684

3579

4474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<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:

0.117

Hom.:

573

Bravo

AF:

0.137

Asia WGS

AF:

0.0920

AC:

318

AN:

3478

EpiCase

AF:

0.0955

EpiControl

AF:

0.0971

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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 12, 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

-0.54

CADD

Benign

0.54

(source)

DANN

Benign

0.87

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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