rs144233940

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000401500.7(WDR62):ā€‹c.3368A>Cā€‹(p.Gln1123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1123R) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.000051 ( 1 hom. )

Consequence

WDR62
ENST00000401500.7 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.982
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09096995).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR62NM_001083961.2 linkuse as main transcriptc.3368A>C p.Gln1123Pro missense_variant 28/32 ENST00000401500.7 NP_001077430.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR62ENST00000401500.7 linkuse as main transcriptc.3368A>C p.Gln1123Pro missense_variant 28/321 NM_001083961.2 ENSP00000384792 P4O43379-4

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000598
AC:
15
AN:
250978
Hom.:
0
AF XY:
0.0000737
AC XY:
10
AN XY:
135752
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000513
AC:
75
AN:
1461798
Hom.:
1
Cov.:
31
AF XY:
0.0000564
AC XY:
41
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000603
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000436
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 31, 2023This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1123 of the WDR62 protein (p.Gln1123Pro). This variant is present in population databases (rs144233940, gnomAD 0.009%). 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: 586941). 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. -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsAug 20, 2018- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 09, 2021The c.3368A>C (p.Q1123P) alteration is located in exon 28 (coding exon 28) of the WDR62 gene. This alteration results from a A to C substitution at nucleotide position 3368, causing the glutamine (Q) at amino acid position 1123 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
1.9
DANN
Benign
0.56
DEOGEN2
Benign
0.011
.;T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.041
N
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.091
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.55
.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.032
Sift
Benign
0.24
T;T
Sift4G
Benign
0.25
T;T
Polyphen
0.67
P;P
Vest4
0.21
MVP
0.45
MPC
0.47
ClinPred
0.32
T
GERP RS
-2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144233940; hg19: chr19-36593882; API