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
NM_172364.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.77
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]
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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
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA2D4 | ENST00000382722.10 | c.2406C>A | p.Tyr802* | stop_gained | Exon 25 of 38 | 1 | NM_172364.5 | ENSP00000372169.4 | ||
| CACNA2D4 | ENST00000586184.5 | c.2406C>A | p.Tyr802* | stop_gained | Exon 25 of 37 | 5 | ENSP00000465060.1 | |||
| CACNA2D4 | ENST00000587995.5 | c.2331C>A | p.Tyr777* | stop_gained | Exon 24 of 37 | 5 | ENSP00000465372.1 | |||
| CACNA2D4 | ENST00000585708.5 | c.2214C>A | p.Tyr738* | stop_gained | Exon 25 of 37 | 5 | ENSP00000467697.1 | |||
| CACNA2D4 | ENST00000588077.5 | c.2214C>A | p.Tyr738* | stop_gained | Exon 25 of 38 | 5 | ENSP00000468530.1 | |||
| CACNA2D4 | ENST00000444595.6 | n.*652C>A | non_coding_transcript_exon_variant | Exon 25 of 37 | 1 | ENSP00000403371.2 | ||||
| CACNA2D4 | ENST00000537784.5 | n.246C>A | non_coding_transcript_exon_variant | Exon 3 of 15 | 1 | ENSP00000440231.2 | ||||
| CACNA2D4 | ENST00000444595.6 | n.*652C>A | 3_prime_UTR_variant | Exon 25 of 37 | 1 | ENSP00000403371.2 |
Frequencies
GnomAD3 genomes 0.000539 AC: 82AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000408 AC: 101AN: 247676Hom.: 0 AF XY: 0.000372 AC XY: 50AN XY: 134428
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GnomAD4 exome AF: 0.000880 AC: 1286AN: 1461134Hom.: 0 Cov.: 30 AF XY: 0.000872 AC XY: 634AN XY: 726754
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GnomAD4 genome 0.000539 AC: 82AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74364
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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
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 22, 2019 | - - |
not provided Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2021 | 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) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 26, 2024 | 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. - |
CACNA2D4-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2024 | 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at