rs55971855

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.2987T>C(p.Phe996Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0069 in 1,572,600 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F996V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 50 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.21

Publications

10 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00739339).

BP6

Variant 12-1799683-A-G is Benign according to our data. Variant chr12-1799683-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AD,Unknown,AR gene

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.2987T>C	p.Phe996Ser	missense	Exon 34 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.2987T>C	p.Phe996Ser	missense	Exon 34 of 38	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5	TSL:5	c.2987T>C	p.Phe996Ser	missense	Exon 34 of 37	ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5	TSL:5	c.2912T>C	p.Phe971Ser	missense	Exon 33 of 37	ENSP00000465372.1	K7EJY1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

783

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00509

AC:

958

AN:

188040

AF XY:

0.00510

show subpopulations

Gnomad AFR exome

AF:

0.000784

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00744

Gnomad OTH exome

AF:

0.00660

GnomAD4 exome

AF:

0.00708

AC:

10060

AN:

1420324

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

4896

AN XY:

702792

show subpopulations

African (AFR)

AF:

0.00139

AC:

AN:

32412

American (AMR)

AF:

0.00426

AC:

164

AN:

38542

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

417

AN:

25372

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37138

South Asian (SAS)

AF:

0.00118

AC:

AN:

80426

European-Finnish (FIN)

AF:

0.00231

AC:

117

AN:

50544

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00795

AC:

8677

AN:

1091222

Other (OTH)

AF:

0.00769

AC:

453

AN:

58936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

505

1010

1515

2020

2525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.00515

AC:

784

AN:

152276

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

349

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41558

American (AMR)

AF:

0.00699

AC:

107

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00787

AC:

535

AN:

68016

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00718

Hom.:

Bravo

AF:

0.00558

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00143

AC:

ESP6500EA

AF:

0.00631

AC:

ExAC

AF:

0.00359

AC:

427

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Retinal cone dystrophy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.039

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.94

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PhyloP100

6.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.7

REVEL

Benign

0.18

Sift

Benign

0.39

Sift4G

Uncertain

0.041

Polyphen

0.93

Vest4

0.49

MVP

0.33

MPC

0.26

ClinPred

0.016

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.55

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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