12-1844466-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_172364.5(CACNA2D4):c.2406C>A(p.Tyr802*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y802Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

CACNA2D4
NM_172364.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 2.77

Publications

14 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-1844466-G-T is Pathogenic according to our data. Variant chr12-1844466-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2504.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2406C>A	p.Tyr802*	stop_gained	Exon 25 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA2D4	ENST00000382722.10 link	c.2406C>A	p.Tyr802*	stop_gained	Exon 25 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5 link	c.2406C>A	p.Tyr802*	stop_gained	Exon 25 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5 link	c.2331C>A	p.Tyr777*	stop_gained	Exon 24 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5 link	c.2214C>A	p.Tyr738*	stop_gained	Exon 25 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5 link	c.2214C>A	p.Tyr738*	stop_gained	Exon 25 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6 link	n.*652C>A		non_coding_transcript_exon_variant	Exon 25 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000537784.5 link	n.246C>A		non_coding_transcript_exon_variant	Exon 3 of 15	1		ENSP00000440231.2
CACNA2D4	ENST00000444595.6 link	n.*652C>A		3_prime_UTR_variant	Exon 25 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

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:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000408

AC:

101

AN:

247676

AF XY:

0.000372

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000783

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000880

AC:

1286

AN:

1461134

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

726754

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000336

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00111

AC:

1229

AN:

1111696

Other (OTH)

AF:

0.000613

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<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:

0.000539

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41464

American (AMR)

AF:

0.000981

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

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:

0.000843

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.00135

AC:

ESP6500AA

AF:

0.000729

AC:

ESP6500EA

AF:

0.000833

AC:

ExAC

AF:

0.000405

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000891

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinal cone dystrophy 4

Pathogenic:2

Nov 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 19, 2025

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1Uncertain:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr802*) in the CACNA2D4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA2D4 cause disease. This variant is present in population databases (rs71454844, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with CACNA2D4-related conditions (PMID: 17033974, 36460718). ClinVar contains an entry for this variant (Variation ID: 2504). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Mar 10, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17033974, 26218913, 31980526, 32967234, 32607809)

not specified

Uncertain:2

Nov 20, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic.

Jul 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA2D4 c.2406C>A (p.Tyr802X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant allele was found at a frequency of 0.00041 in 247676 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA2D4 causing Retinal Cone Dystrophy 4, allowing no conclusion about variant significance. c.2406C>A has been observed in individual(s) affected with CACNA2D4-related conditions (examples: Wycisk_2006, Karali_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Retinal Cone Dystrophy 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36460718, 17033974). ClinVar contains an entry for this variant (Variation ID: 2504). Based on the evidence outlined above, the variant was classified as uncertain significance.

CACNA2D4-related disorder

Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CACNA2D4 c.2406C>A variant is predicted to result in premature protein termination (p.Tyr802*). This variant has been reported in the homozygous state in two siblings with a mild, progressive cone dystrophy; it was found to be heterozygous in an unaffected parent and absent from two additional unaffected siblings (Wycisk et al. 2006. PubMed ID: 17033974). This variant has also been reported in an individual with an inherited retinal disease as part of a genetically solved cohort, although no additional details were provided (Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.078% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in CACNA2D4 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

LIST_S2

Benign

0.0

.;.;.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.;.;.

PhyloP100

2.8

PROVEAN

Benign

0.0

.;.;.;.;.;.

Sift

Pathogenic

0.0

.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;.

Vest4

0.40

GERP RS

2.2

Mutation Taster

=0/200

disease causing (ClinVar)

(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