rs2074435

chr19-36103757-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083961.2(WDR62):c.3929A>T(p.Gln1310Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,610,952 control chromosomes in the GnomAD database, including 319,407 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35415 hom., cov: 33)
  • Exomes 𝑓: 0.62 (283992 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1123858E-6).
• BP6: Variant 19-36103757-A-T is Benign according to our data. Variant chr19-36103757-A-T is described in ClinVar as [Benign]. Clinvar id is 93538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36103757-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.3929A>T	p.Gln1310Leu	missense_variant	30/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.3929A>T	p.Gln1310Leu	missense_variant	30/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102797 AN: 152006 Hom.: 35370 Cov.: 33

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.675

GnomAD3 exomes AF: 0.657 AC: 163767 AN: 249138 Hom.: 54611 AF XY: 0.647 AC XY: 87355 AN XY: 134952

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.761

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.777

Gnomad SAS exome AF: 0.614

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.622 AC: 906857 AN: 1458828 Hom.: 283992 Cov.: 88 AF XY: 0.621 AC XY: 450666 AN XY: 725884

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.759

Gnomad4 ASJ exome AF: 0.588

Gnomad4 EAS exome AF: 0.800

Gnomad4 SAS exome AF: 0.613

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.605

Gnomad4 OTH exome AF: 0.628

GnomAD4 genome AF: 0.676 AC: 102900 AN: 152124 Hom.: 35415 Cov.: 33 AF XY: 0.679 AC XY: 50473 AN XY: 74358

Gnomad4 AFR AF: 0.788

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.593

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.617

Gnomad4 FIN AF: 0.654

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.676

Alfa AF: 0.633 Hom.: 7257

Bravo AF: 0.687

TwinsUK AF: 0.604 AC: 2239

ALSPAC AF: 0.602 AC: 2321

ESP6500AA AF: 0.783 AC: 3451

ESP6500EA AF: 0.605 AC: 5204

ExAC AF: 0.653 AC: 79225

Asia WGS AF: 0.727 AC: 2528 AN: 3478

EpiCase AF: 0.614

EpiControl AF: 0.608

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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:4

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.1
Dann	Benign	0.71
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0000011	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.026
Sift	Benign	0.19	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;B
Vest4		0.036
MPC		0.21
ClinPred		0.0057	T
GERP RS		2.1
Varity_R		0.053
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2074435; hg19: chr19-36594659; COSMIC: COSV54332369;