rs61742664

Positions:

• chr19-36058782-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083961.2(WDR62):​c.180G>A​(p.Val60=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,613,680 control chromosomes in the GnomAD database, including 4,355 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (405 hom., cov: 33)
  • Exomes 𝑓: 0.052 (3950 hom.)
• Consequence: WDR62 NM_001083961.2 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.38

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-36058782-G-A is Benign according to our data. Variant chr19-36058782-G-A is described in ClinVar as [Benign]. Clinvar id is 160258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36058782-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.180G>A	p.Val60=	splice_region_variant, synonymous_variant	2/32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.180G>A	p.Val60=	splice_region_variant, synonymous_variant	2/32	1	NM_001083961.2	ENSP00000384792	P4

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7558 AN: 152200 Hom.: 403 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0568

GnomAD3 exomes AF: 0.0805 AC: 20196 AN: 250918 Hom.: 1433 AF XY: 0.0838 AC XY: 11372 AN XY: 135718

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0664

GnomAD4 exome AF: 0.0522 AC: 76238 AN: 1461362 Hom.: 3950 Cov.: 31 AF XY: 0.0562 AC XY: 40832 AN XY: 727020

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.0710

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.0358

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0658

GnomAD4 genome AF: 0.0497 AC: 7570 AN: 152318 Hom.: 405 Cov.: 33 AF XY: 0.0533 AC XY: 3971 AN XY: 74468

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.0789

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.0328

Gnomad4 NFE AF: 0.0367

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0389 Hom.: 65

Bravo AF: 0.0479

Asia WGS AF: 0.261 AC: 907 AN: 3478

EpiCase AF: 0.0388

EpiControl AF: 0.0359

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61742664; hg19: chr19-36549684; COSMIC: COSV99495663; COSMIC: COSV99495663;