rs35811023

chr19-36103774-C-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.3946C>G(p.Gln1316Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,610,452 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1316Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (24 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.453

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=0.0041314065).
• BP6: Variant 19-36103774-C-G is Benign according to our data. Variant chr19-36103774-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 93539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36103774-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00405 (617/152184) while in subpopulation NFE AF= 0.00688 (468/67984). AF 95% confidence interval is 0.00637. There are 2 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.3946C>G	p.Gln1316Glu	missense_variant	30/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.3946C>G	p.Gln1316Glu	missense_variant	30/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152062 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00401 AC: 997 AN: 248818 Hom.: 4 AF XY: 0.00398 AC XY: 536 AN XY: 134796

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000664

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00578 AC: 8425 AN: 1458268 Hom.: 24 Cov.: 36 AF XY: 0.00555 AC XY: 4030 AN XY: 725558

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000895

Gnomad4 NFE exome AF: 0.00698

Gnomad4 OTH exome AF: 0.00461

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152184 Hom.: 2 Cov.: 33 AF XY: 0.00339 AC XY: 252 AN XY: 74406

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00688

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00598 Hom.: 2

Bravo AF: 0.00466

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00384 AC: 466

EpiCase AF: 0.00802

EpiControl AF: 0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WDR62: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2014	- -

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.5
Dann	Benign	0.32
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.024
Sift	Benign	0.48	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MVP		0.38
MPC		0.24
ClinPred		0.0033	T
GERP RS		1.5
Varity_R		0.069
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35811023; hg19: chr19-36594676; COSMIC: COSV105820141;