17-1727526-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001163809.2(WDR81):c.2567C>T(p.Pro856Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000903 in 1,550,304 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001163809.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000129 AC: 2AN: 154980Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82538
GnomAD4 exome AF: 0.00000286 AC: 4AN: 1398104Hom.: 0 Cov.: 36 AF XY: 0.00000145 AC XY: 1AN XY: 689542
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74362
ClinVar
Submissions by phenotype
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 Pathogenic:2
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Variant summary: WDR81 c.2567C>T (p.Pro856Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 154980 control chromosomes (gnomAD). c.2567C>T has been reported in the literature in the homozygous state in six siblings affected with Cerebellar Ataxia, Intellectual Disability, And Dysequilibrium Syndrome 2 (CAMRQ2) from a large consanguineous Turkish family (Gulsuner_2011). The variant was found to segregate with the disease phenotype in this kindred, where over 100 family members spanning 5 generations were sequenced. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21885617). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2;C4747885:Hydrocephalus, congenital, 3, with brain anomalies Pathogenic:2
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not provided Pathogenic:1
Published functional studies demonstrate impaired autophagic clearance of protein aggregates and maintenance of cell viability (PMID: 33730050); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28969387, 22686558, 16371500, 33996189, 33724704, 34338917, 21885617, 33730050) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at