rs33912216

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.3330C>T(p.Gly1110Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,612,800 control chromosomes in the GnomAD database, including 8,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 991 hom., cov: 33)

Exomes 𝑓: 0.096 ( 7593 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.38

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):

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=-0.87).

BP6

Variant 12-1793739-G-A is Benign according to our data. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-1793739-G-A is described in CliVar as Benign. Clinvar id is 197051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.3330C>T	p.Gly1110Gly	synonymous_variant	Exon 38 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.3330C>T	p.Gly1110Gly	synonymous_variant	Exon 38 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000587995.5 link	c.3255C>T	p.Gly1085Gly	synonymous_variant	Exon 37 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000588077.5 link	c.3138C>T	p.Gly1046Gly	synonymous_variant	Exon 38 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.768C>T	p.Gly256Gly	synonymous_variant	Exon 12 of 12	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.765C>T	p.Gly255Gly	synonymous_variant	Exon 12 of 12	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.720C>T	p.Gly240Gly	synonymous_variant	Exon 11 of 11	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*1514C>T		non_coding_transcript_exon_variant	Exon 37 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*523C>T		non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*523C>T		non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*523C>T		non_coding_transcript_exon_variant	Exon 11 of 11	5		ENSP00000467333.1	K7EIY9
CACNA2D4	ENST00000444595.6 link	n.*1514C>T		3_prime_UTR_variant	Exon 37 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*523C>T		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*523C>T		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*523C>T		3_prime_UTR_variant	Exon 11 of 11	5		ENSP00000467333.1	K7EIY9

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16322

AN:

152152

Hom.:

992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.0648

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0851

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.114

AC:

28140

AN:

245934

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.0767

Gnomad EAS exome

AF:

0.0537

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0862

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0957

AC:

139733

AN:

1460530

Hom.:

7593

Cov.:

AF XY:

0.0956

AC XY:

69486

AN XY:

726606

show subpopulations

African (AFR)

AF:

0.122

AC:

4088

AN:

33470

American (AMR)

AF:

0.228

AC:

10196

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0757

AC:

1976

AN:

26114

East Asian (EAS)

AF:

0.0528

AC:

2095

AN:

39696

South Asian (SAS)

AF:

0.130

AC:

11234

AN:

86224

European-Finnish (FIN)

AF:

0.111

AC:

5860

AN:

52790

Middle Eastern (MID)

AF:

0.104

AC:

587

AN:

5664

European-Non Finnish (NFE)

AF:

0.0880

AC:

97842

AN:

1111558

Other (OTH)

AF:

0.0970

AC:

5855

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6243

12485

18728

24970

31213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3802

7604

11406

15208

19010

<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:

0.107

AC:

16334

AN:

152270

Hom.:

991

Cov.:

AF XY:

0.109

AC XY:

8149

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.120

AC:

4973

AN:

41538

American (AMR)

AF:

0.189

AC:

2886

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

239

AN:

3468

East Asian (EAS)

AF:

0.0638

AC:

330

AN:

5176

South Asian (SAS)

AF:

0.119

AC:

576

AN:

4828

European-Finnish (FIN)

AF:

0.111

AC:

1183

AN:

10614

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0851

AC:

5789

AN:

68018

Other (OTH)

AF:

0.114

AC:

241

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

756

1512

2268

3024

3780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.100

Hom.:

682

Bravo

AF:

0.115

Asia WGS

AF:

0.102

AC:

356

AN:

3478

EpiCase

AF:

0.0842

EpiControl

AF:

0.0893

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.87

CADD

Benign

0.030

(source)

DANN

Benign

0.73

PhyloP100

-5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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