rs587784541
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_001083961.2(WDR62):c.1043+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00012 in 1,612,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
WDR62
NM_001083961.2 splice_donor_region, intron
NM_001083961.2 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 6.55
Genes affected
WDR62 (HGNC:24502): (WD repeat domain 62) This gene is proposed to play a role in cerebral cortical development. Mutations in this gene have been associated with microencephaly, cortical malformations, and cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
?
Variant 19-36071719-A-G is Pathogenic according to our data. Variant chr19-36071719-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160243.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=4, Likely_pathogenic=2}. Variant chr19-36071719-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR62 | NM_001083961.2 | c.1043+3A>G | splice_donor_region_variant, intron_variant | ENST00000401500.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR62 | ENST00000401500.7 | c.1043+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_001083961.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152254Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250248Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135298
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GnomAD4 exome AF: 0.000123 AC: 180AN: 1459882Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87AN XY: 725892
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 28, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles | Jan 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary microcephaly 2, with or without cortical malformations (MIM#604317). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 13 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in a homozygous state in two individuals within the DECIPHER cohort with microcephaly, intellectual disability and seizures; one of individuals also had polymicrogyria. At least two affected individuals were also identified by diagnostics laboratories in ClinVar, with one laboratory classifying the variant as likely pathogenic and the other as a variant of uncertain significance. Most recently, the variant has been reported in a homozygous state and a compound heterozygous state in two individuals with microcephaly, intellectual disability and seizures (PMID: 34402213). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 16, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | This sequence change falls in intron 8 of the WDR62 gene. It does not directly change the encoded amino acid sequence of the WDR62 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587784541, gnomAD 0.01%). This variant has been observed in individual(s) with primary microcephaly (PMID: 34402213). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 160243). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at