NM_172364.5:c.2087A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172364.5(CACNA2D4):c.2087A>G(p.His696Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,972 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H696Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 69 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 42 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.02

Publications

7 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 (MetaRNN=0.007865012).

BP6

Variant 12-1856077-T-C is Benign according to our data. Variant chr12-1856077-T-C is described in ClinVar as Benign. ClinVar VariationId is 262813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2195/152304) while in subpopulation AFR AF = 0.0478 (1988/41556). AF 95% confidence interval is 0.0461. There are 69 homozygotes in GnomAd4. There are 1054 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2087A>G	p.His696Arg	missense_variant	Exon 22 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.2087A>G	p.His696Arg	missense_variant	Exon 22 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2087A>G	p.His696Arg	missense_variant	Exon 22 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2012A>G	p.His671Arg	missense_variant	Exon 21 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.1895A>G	p.His632Arg	missense_variant	Exon 22 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.1895A>G	p.His632Arg	missense_variant	Exon 22 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.*333A>G		non_coding_transcript_exon_variant	Exon 22 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000444595.6 link	n.*333A>G		3_prime_UTR_variant	Exon 22 of 37	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2191

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0479

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00379

AC:

945

AN:

249266

AF XY:

0.00298

show subpopulations

Gnomad AFR exome

AF:

0.0453

Gnomad AMR exome

AF:

0.00440

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000655

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00177

AC:

2592

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1180

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0453

AC:

1517

AN:

33468

American (AMR)

AF:

0.00445

AC:

199

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000495

AC:

550

AN:

1111850

Other (OTH)

AF:

0.00460

AC:

278

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

146

292

437

583

729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0144

AC:

2195

AN:

152304

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0478

AC:

1988

AN:

41556

American (AMR)

AF:

0.00908

AC:

139

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68032

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

208

313

417

521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00487

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0380

AC:

153

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00436

AC:

527

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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

Benign

0.19

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0079

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;.;.;M;.;.

PhyloP100

8.0

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.1

D;.;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.20

T;.;.;.;.;.

Sift4G

Benign

0.11

T;T;T;T;T;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.86

MVP

0.42

MPC

0.61

ClinPred

0.025

GERP RS

4.2

Varity_R

0.56

gMVP

0.72

Mutation Taster

=90/10

polymorphism

(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