rs587776900

Positions:

• chr19-36103758-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001083961.2(WDR62):​c.3936dup​(p.Val1313ArgfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: WDR62 NM_001083961.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.923

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-36103758-G-GC is Pathogenic according to our data. Variant chr19-36103758-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 31038.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.3936dup	p.Val1313ArgfsTer18	frameshift_variant	30/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.3936dup	p.Val1313ArgfsTer18	frameshift_variant	30/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458552 Hom.: 0 Cov.: 36 AF XY: 0.00000827 AC XY: 6 AN XY: 725746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	Jan 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 21961505, 31258591, 33921653, 33937237, 24228726, 25303973, 35726608, 21496009, 34402213, 20890279, 32677750, 20890278) -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587776900; hg19: chr19-36594660;