12-1844466-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

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). 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

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 id is 2504.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}. Variant chr12-1844466-G-T is described in Lovd as [Likely_pathogenic].

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	Q7Z3S7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2406C>A	p.Tyr802*	stop_gained	Exon 25 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2406C>A	p.Tyr802*	stop_gained	Exon 25 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2331C>A	p.Tyr777*	stop_gained	Exon 24 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2214C>A	p.Tyr738*	stop_gained	Exon 25 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2214C>A	p.Tyr738*	stop_gained	Exon 25 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.*652C>A		non_coding_transcript_exon_variant	Exon 25 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.246C>A		non_coding_transcript_exon_variant	Exon 3 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000444595.6 link	n.*652C>A		3_prime_UTR_variant	Exon 25 of 37	1		ENSP00000403371.2	E7EUE0

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

GnomAD3 exomes

AF:

0.000408

AC:

101

AN:

247676

Hom.:

AF XY:

0.000372

AC XY:

AN XY:

134428

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000539

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000871

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

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:2Uncertain:1

Jul 22, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA2D4 c.2406C>A (p.Tyr802Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Tyr802Ter variant has been reported in one study in which it is found in a homozygous state in two siblings with retinal cone dystrophy (Wycisk et al. 2006). The variant allele was absent in the unaffected siblings and present in a heterozygous state in the unaffected father. The p.Tyr802Ter variant was absent from 224 controls and is reported at a frequency of 0.00067 in the European (non-Finnish) population of the Exome Aggregation Consortium. Bacchi et al. (2015) reported that the variant results in the abolition of a predicted exon splicing enhancer and the creation of an exon splicing silencer. Due to the potential impact of stop-gained variants and the supporting evidence from the literature, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for retinal cone dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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) -

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. -

not specified

Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.93

Vest4

0.40

GERP RS

2.2

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over