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):

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 -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 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2987T>C	p.Phe996Ser	missense_variant	Exon 34 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1
CACNA2D4	XM_011521041.3 link	c.2924T>C	p.Phe975Ser	missense_variant	Exon 33 of 36		XP_011519343.1
CACNA2D4	XM_047429897.1 link	c.2915T>C	p.Phe972Ser	missense_variant	Exon 33 of 36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2987T>C	p.Phe996Ser	missense_variant	Exon 34 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2987T>C	p.Phe996Ser	missense_variant	Exon 34 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2912T>C	p.Phe971Ser	missense_variant	Exon 33 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2795T>C	p.Phe932Ser	missense_variant	Exon 34 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2795T>C	p.Phe932Ser	missense_variant	Exon 34 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.425T>C	p.Phe142Ser	missense_variant	Exon 8 of 12	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.422T>C	p.Phe141Ser	missense_variant	Exon 8 of 12	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.377T>C	p.Phe126Ser	missense_variant	Exon 7 of 11	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*1171T>C		non_coding_transcript_exon_variant	Exon 33 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*180T>C		non_coding_transcript_exon_variant	Exon 11 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*180T>C		non_coding_transcript_exon_variant	Exon 6 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*180T>C		non_coding_transcript_exon_variant	Exon 7 of 11	5		ENSP00000467333.1	K7EIY9
CACNA2D4	ENST00000444595.6 link	n.*1171T>C		3_prime_UTR_variant	Exon 33 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*180T>C		3_prime_UTR_variant	Exon 11 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*180T>C		3_prime_UTR_variant	Exon 6 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*180T>C		3_prime_UTR_variant	Exon 7 of 11	5		ENSP00000467333.1	K7EIY9

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA2D4: BS2 -

Feb 01, 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

- -

not specified

Benign:2

Oct 02, 2013

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

- -

Retinal cone dystrophy 4

Benign:1

Jan 13, 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

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

T;.;.;.;.;.;.

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.94

MetaRNN

Benign

0.0074

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

L;.;.;.;.;L;.

PhyloP100

6.2

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.7

N;N;.;.;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.39

T;D;.;.;.;.;.

Sift4G

Uncertain

0.041

D;D;T;D;D;D;D

Polyphen

0.93

P;P;.;B;.;.;.

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

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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