rs1008328

Positions:

• chr19-36104534-A-C
• chr19-36104534-A-G
• chr19-36104534-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.4170A>C​(p.Leu1390Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,613,644 control chromosomes in the GnomAD database, including 469,035 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 0.75 (42774 hom., cov: 32)
  • Exomes 𝑓: 0.76 (426261 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.126

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=9.692469E-7).
• BP6: Variant 19-36104534-A-C is Benign according to our data. Variant chr19-36104534-A-C is described in ClinVar as [Benign]. Clinvar id is 160301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36104534-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.4170A>C	p.Leu1390Phe	missense_variant	31/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.4170A>C	p.Leu1390Phe	missense_variant	31/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113841 AN: 151982 Hom.: 42761 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.759

GnomAD3 exomes AF: 0.750 AC: 188442 AN: 251128 Hom.: 71255 AF XY: 0.745 AC XY: 101160 AN XY: 135750

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.760

Gnomad EAS exome AF: 0.750

Gnomad SAS exome AF: 0.606

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.762 AC: 1114342 AN: 1461544 Hom.: 426261 Cov.: 76 AF XY: 0.759 AC XY: 551863 AN XY: 727086

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.806

Gnomad4 ASJ exome AF: 0.752

Gnomad4 EAS exome AF: 0.769

Gnomad4 SAS exome AF: 0.617

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.774

Gnomad4 OTH exome AF: 0.749

GnomAD4 genome AF: 0.749 AC: 113895 AN: 152100 Hom.: 42774 Cov.: 32 AF XY: 0.748 AC XY: 55623 AN XY: 74330

Gnomad4 AFR AF: 0.699

Gnomad4 AMR AF: 0.786

Gnomad4 ASJ AF: 0.759

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.782

Gnomad4 NFE AF: 0.777

Gnomad4 OTH AF: 0.757

Alfa AF: 0.773 Hom.: 49800

Bravo AF: 0.751

TwinsUK AF: 0.770 AC: 2854

ALSPAC AF: 0.769 AC: 2965

ESP6500AA AF: 0.696 AC: 3066

ESP6500EA AF: 0.776 AC: 6676

ExAC AF: 0.742 AC: 90139

Asia WGS AF: 0.636 AC: 2212 AN: 3478

EpiCase AF: 0.782

EpiControl AF: 0.785

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2014	- -

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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	Athena Diagnostics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.54
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.083	T;T
MetaRNN	Benign	9.7e-7	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.055
Sift	Benign	0.31	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0020	B;B
Vest4		0.029
MutPred		0.36		.;Loss of phosphorylation at S1388 (P = 0.1262);
MPC		0.24
ClinPred		0.0034	T
GERP RS		2.0
Varity_R		0.047
gMVP		0.045

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: rs1008328; hg19: chr19-36595436; COSMIC: COSV54335267;