chr12-1792998-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000444595.6(CACNA2D4):n.*2255G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 152,054 control chromosomes in the GnomAD database, including 16,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 16538 hom., cov: 32)

Exomes 𝑓: 0.43 ( 7 hom. )

Consequence

CACNA2D4
ENST00000444595.6 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.11

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 12-1792998-C-T is Benign according to our data. Variant chr12-1792998-C-T is described in ClinVar as Benign. ClinVar VariationId is 307819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.*657G>A		3_prime_UTR_variant	Exon 38 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000444595.6 link	n.*2255G>A	non_coding_transcript_exon_variant	Exon 37 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*1264G>A	non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*1264G>A	non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000382722.10 link	c.*657G>A	3_prime_UTR_variant	Exon 38 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000444595.6 link	n.*2255G>A	3_prime_UTR_variant	Exon 37 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*1264G>A	3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*1264G>A	3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000587995.5 link	c.*657G>A	downstream_gene_variant		5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000538450.5 link	c.*657G>A	downstream_gene_variant		2		ENSP00000446341.1	B4DVU4

Frequencies

GnomAD3 genomes

AF:

0.434

AC:

65990

AN:

151878

Hom.:

16536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.622

Gnomad AMR

AF:

0.396

Gnomad ASJ

AF:

0.588

Gnomad EAS

AF:

0.481

Gnomad SAS

AF:

0.452

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.545

Gnomad NFE

AF:

0.564

Gnomad OTH

AF:

0.424

GnomAD4 exome

AF:

0.431

AC:

AN:

Hom.:

Cov.:

AF XY:

0.344

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.750

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.469

AC:

AN:

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.434

AC:

65996

AN:

151996

Hom.:

16538

Cov.:

AF XY:

0.434

AC XY:

32277

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.180

AC:

7461

AN:

41446

American (AMR)

AF:

0.396

AC:

6050

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

2041

AN:

3470

East Asian (EAS)

AF:

0.482

AC:

2491

AN:

5166

South Asian (SAS)

AF:

0.452

AC:

2176

AN:

4818

European-Finnish (FIN)

AF:

0.552

AC:

5832

AN:

10562

Middle Eastern (MID)

AF:

0.555

AC:

162

AN:

292

European-Non Finnish (NFE)

AF:

0.564

AC:

38324

AN:

67956

Other (OTH)

AF:

0.423

AC:

893

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1717

3433

5150

6866

8583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.488

Hom.:

13386

Bravo

AF:

0.411

Asia WGS

AF:

0.424

AC:

1479

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.35

(source)

DANN

Benign

0.54

PhyloP100

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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