rs535488873
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001083961.2(WDR62):c.589G>A(p.Val197Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
WDR62
NM_001083961.2 missense
NM_001083961.2 missense
Scores
3
3
12
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.044121265).
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000115 (168/1461850) while in subpopulation SAS AF= 0.00154 (133/86258). AF 95% confidence interval is 0.00133. There are 1 homozygotes in gnomad4_exome. There are 117 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR62 | NM_001083961.2 | c.589G>A | p.Val197Ile | missense_variant | 6/32 | ENST00000401500.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR62 | ENST00000401500.7 | c.589G>A | p.Val197Ile | missense_variant | 6/32 | 1 | NM_001083961.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152198Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000199 AC: 50AN: 251352Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135854
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GnomAD4 exome AF: 0.000115 AC: 168AN: 1461850Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 117AN XY: 727226
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74468
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 197 of the WDR62 protein (p.Val197Ile). This variant is present in population databases (rs535488873, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with WDR62-related conditions. ClinVar contains an entry for this variant (Variation ID: 160306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WDR62 protein function. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
D;D;.
Vest4
MutPred
Loss of methylation at K196 (P = 0.0968);Loss of methylation at K196 (P = 0.0968);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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