rs182467995

Positions:

• chr19-36104763-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083961.2(WDR62):​c.4312-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,760 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (7 hom.)
• Consequence: WDR62 NM_001083961.2 splice_region, intron
• Scores: Splicing: ADA: 0.1068
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: 0.0100

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]

WDR62 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-36104763-T-G is Benign according to our data. Variant chr19-36104763-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 160302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00212 (323/152334) while in subpopulation NFE AF= 0.00391 (266/68018). AF 95% confidence interval is 0.00352. There are 2 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.4312-5T>G		splice_region_variant, intron_variant		ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.4312-5T>G		splice_region_variant, intron_variant		1	NM_001083961.2	ENSP00000384792.1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00210 AC: 526 AN: 250210 Hom.: 0 AF XY: 0.00214 AC XY: 290 AN XY: 135448

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00340

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00338 AC: 4933 AN: 1461426 Hom.: 7 Cov.: 34 AF XY: 0.00330 AC XY: 2398 AN XY: 727030

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.000529

Gnomad4 NFE exome AF: 0.00398

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74486

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00303 Hom.: 1

Bravo AF: 0.00193

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	WDR62: BP4, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2013	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.0
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.10		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: rs182467995; hg19: chr19-36595665;