rs786205249
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_StrongPM2PP3_ModeratePP5_Very_Strong
The NM_145200.5(CABP4):c.800_801del variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000223 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
CABP4
NM_145200.5 splice_acceptor
NM_145200.5 splice_acceptor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
CABP4 (HGNC:1386): (calcium binding protein 4) This gene encodes a member of the CABP family of calcium binding protein characterized by four EF-hand motifs. Mutations in this gene are associated with congenital stationary night blindness type 2B. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 3.7693236 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: cctgcccttctctcccgcAGttt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-67458628-CAG-C is Pathogenic according to our data. Variant chr11-67458628-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67458628-CAG-C is described in Lovd as [Pathogenic]. Variant chr11-67458628-CAG-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CABP4 | NM_145200.5 | c.800_801del | splice_acceptor_variant | ENST00000325656.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CABP4 | ENST00000325656.7 | c.800_801del | splice_acceptor_variant | 1 | NM_145200.5 | P1 | |||
CABP4 | ENST00000438189.6 | c.485_486del | splice_acceptor_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251246Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135844
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461812Hom.: 0 AF XY: 0.0000151 AC XY: 11AN XY: 727208
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74314
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2019 | The c.800_801delAG variant in the CABP4 gene has been reported previously in association with autosomal recessive cone-rod synaptic disorder (Zeitz et al., 2006). The c.800_801delAG variant causes a frameshift starting with codon Glutamic Acid 267, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 92 of the new reading frame, denoted p.Glu267ValfsX92. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 9 amino acids are lost and replaced by 91 incorrect amino acids. Functional studies of the c.800_801delAG variant demonstrate a damaging effect with reduction in Ca(2+) channel availability and loss of Ca(2+) channel function (Shaltiel et al., 2012). The c.800_801delAG variant is observed in 8/111584 (0.007%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.800_801delAG as a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change results in a frameshift in the CABP4 gene (p.Glu267Valfs*92). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the CABP4 protein and extend the protein by 82 additional amino acid residues. This variant is present in population databases (rs755955765, gnomAD 0.007%). This frameshift has been observed in individuals with congenital non-progressive cone-rod synaptic disorder (PMID: 16960802). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1952). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2018 | - - |
Cone-rod synaptic disorder, congenital nonprogressive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2006 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 5
DS_AL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at