rs61494900

Positions:

• chr19-36092749-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.2271G>A​(p.Leu757=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,952 control chromosomes in the GnomAD database, including 10,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1794 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8664 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.716

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=-0.47).
• BP6: Variant 19-36092749-G-A is Benign according to our data. Variant chr19-36092749-G-A is described in ClinVar as [Benign]. Clinvar id is 160263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36092749-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.716 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.2271G>A	p.Leu757=	synonymous_variant	19/32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.2271G>A	p.Leu757=	synonymous_variant	19/32	1	NM_001083961.2	ENSP00000384792	P4

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20997 AN: 152024 Hom.: 1794 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0893

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.104 AC: 26257 AN: 251408 Hom.: 1727 AF XY: 0.105 AC XY: 14235 AN XY: 135892

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0746

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0910

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.104 AC: 152177 AN: 1461810 Hom.: 8664 Cov.: 33 AF XY: 0.104 AC XY: 75935 AN XY: 727204

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.0783

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.138 AC: 21012 AN: 152142 Hom.: 1794 Cov.: 32 AF XY: 0.137 AC XY: 10164 AN XY: 74392

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0894

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.157

Alfa AF: 0.127 Hom.: 595

Bravo AF: 0.143

Asia WGS AF: 0.0520 AC: 183 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.130

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.47
CADD	Benign	10
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61494900; hg19: chr19-36583651;