rs147875659

chr19-36084678-G-Achr19-36084678-G-Cchr19-36084678-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PP5_Strong BS1_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:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:10
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a repeat WD 7 (size 39) in uniprot entity WDR62_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001083961.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-36084678-G-A is Pathogenic according to our data. Variant chr19-36084678-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 41.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=10, Pathogenic=1, Likely_pathogenic=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000129 (189/1461682) while in subpopulation MID AF= 0.00382 (22/5764). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4_exome. There are 98 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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.1576G>A	p.Glu526Lys	missense_variant	12/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.1576G>A	p.Glu526Lys	missense_variant	12/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251202 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000129 AC: 189 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74274

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Pathogenic:1 Uncertain:5

Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 17, 2021	- -
Pathogenic, flagged submission	literature only	OMIM	Sep 09, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 17, 2018	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├╝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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	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

Likely pathogenic, flagged submission

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 07, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.051	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;D
Vest4		0.88
MVP		0.92
MPC		0.86
ClinPred		0.62	D
GERP RS		5.2
Varity_R		0.50
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs147875659; hg19: chr19-36575580;