chr12-1800379-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_172364.5(CACNA2D4):c.2921+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,880 control chromosomes in the GnomAD database, including 3 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

CACNA2D4
NM_172364.5 splice_region, intron

Scores

Splicing: ADA: 0.00004731

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.332

Publications

1 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:

LOC105369602 (HGNC:):

LOC105369602 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-1800379-C-G is Benign according to our data. Variant chr12-1800379-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2921+7G>C		splice_region_variant, intron_variant	Intron 32 of 37	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2921+7G>C	splice_region_variant, intron_variant	Intron 32 of 37	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2921+7G>C	splice_region_variant, intron_variant	Intron 32 of 36	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2846+7G>C	splice_region_variant, intron_variant	Intron 31 of 36	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2729+7G>C	splice_region_variant, intron_variant	Intron 32 of 36	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2729+7G>C	splice_region_variant, intron_variant	Intron 32 of 37	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.359+7G>C	splice_region_variant, intron_variant	Intron 6 of 11	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.356+7G>C	splice_region_variant, intron_variant	Intron 6 of 11	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.311+7G>C	splice_region_variant, intron_variant	Intron 5 of 10	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*1105+7G>C	splice_region_variant, intron_variant	Intron 31 of 36	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*114+7G>C	splice_region_variant, intron_variant	Intron 9 of 14	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*114+7G>C	splice_region_variant, intron_variant	Intron 4 of 9	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*114+7G>C	splice_region_variant, intron_variant	Intron 5 of 10	5		ENSP00000467333.1	K7EIY9

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

375

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00859

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000619

AC:

153

AN:

247096

AF XY:

0.000477

show subpopulations

Gnomad AFR exome

AF:

0.00873

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00956

AC:

320

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111762

Other (OTH)

AF:

0.000762

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00247

AC:

376

AN:

152296

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00859

AC:

357

AN:

41542

American (AMR)

AF:

0.000719

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000291

Hom.:

Bravo

AF:

0.00300

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2013

Eurofins Ntd Llc (ga)

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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.3

(source)

DANN

Benign

0.48

PhyloP100

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.0

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