rs147875659
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP5_StrongBS1_Supporting
The NM_001083961.2(WDR62):c.1576G>A(p.Glu526Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001083961.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152096Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000104 AC: 26AN: 251202Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135770
GnomAD4 exome AF: 0.000129 AC: 189AN: 1461682Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98AN XY: 727150
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152096Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74274
ClinVar
Submissions by phenotype
Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Pathogenic:1Uncertain:5
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
The WDR62 c.1576G>A (p.Glu526Lys) variant is a missense variant has been reported in one study, in which it is found in a homozygous state in one individual born to consanguineous Turkish parents, affected with microcephaly, intellectual disability, prognathism, dysconjugate gaze, and dysarthria (Bilg├â•var et al. 2010). The p.Glu526Lys variant was present in 3 of 1290 unrelated Turkish control chromosomes, absent from 1500 Caucasian control chromosomes, and is reported at a frequency of 0.000415 in the Other population of the Genome Aggregation Database. Based on the limited evidence, the p.Glu526Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for primary microcephaly 2 with or without cortical malformations. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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not provided Uncertain:4
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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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 41). This missense change has been observed in individual(s) with primary microcephaly (PMID: 20729831, 31130284). This variant is present in population databases (rs147875659, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 526 of the WDR62 protein (p.Glu526Lys). -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28756000, 20729831, 31130284, 31980526, 31258591, 21961505, 25303973, 24228726, 23065275, 34426522) -
Autosomal recessive primary microcephaly Pathogenic:1
Variant summary: WDR62 c.1576G>A (p.Glu526Lys) results in a conservative amino acid change located in the WD40-repeat-containing domain (IPR017986) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 285130 control chromosomes (gnomAD, Bilguvar_2010). c.1576G>A has been reported in the literature in at least two homozygous individuals affected with neurological malformations and intellectual disability (Bilguvar_2010, Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Inborn genetic diseases Uncertain:1
The c.1576G>A (p.E526K) alteration is located in exon 12 (coding exon 12) of the WDR62 gene. This alteration results from a G to A substitution at nucleotide position 1576, causing the glutamic acid (E) at amino acid position 526 to be replaced by a lysine (K). (Bilgüvar, 2010), (Monies, 2019) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at