rs587784543

chr19-36083171-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001083961.2(WDR62):c.1480G>A(p.Gly494Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 9.49

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 19-36083171-G-A is Pathogenic according to our data. Variant chr19-36083171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160249.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.1480G>A	p.Gly494Arg	missense_variant	11/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.1480G>A	p.Gly494Arg	missense_variant	11/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000526 AC: 13 AN: 247098 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1460022 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 726090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74496

Gnomad4 AFR AF: 0.00

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 27, 2022	PP1, PP4, PM2, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 494 of the WDR62 protein (p.Gly494Arg). This variant is present in population databases (rs587784543, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Seckel syndrome (PMID: 33604570). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 160249). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 submitter	clinical testing	GeneDx	Feb 07, 2022	Not observed at significant frequency in large population cohorts (gnomAD); 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: 31589614, 33604570) -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 31, 2013	- -

Abnormal cerebral morphology Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

-

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.61		Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);
MVP		0.78
MPC		0.91
ClinPred		0.82	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587784543; hg19: chr19-36574073; COSMIC: COSV54332964;