rs45470992

Variant names:

• chr19-36103467-C-T
• rs45470992
• NM_001083961.2:c.3639C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083961.2(WDR62):​c.3639C>T​(p.Ser1213Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,614,136 control chromosomes in the GnomAD database, including 1,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1298 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.687
• Publications: 11 publications found

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]

WDR62 Gene-Disease associations (from GenCC):

• microcephaly 2, primary, autosomal recessive, with or without cortical malformations

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P, ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-36103467-C-T is Benign according to our data. Variant chr19-36103467-C-T is described in ClinVar as Benign. ClinVar VariationId is 160294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.3639C>T	p.Ser1213Ser	synonymous_variant	Exon 30 of 32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.3639C>T	p.Ser1213Ser	synonymous_variant	Exon 30 of 32	1	NM_001083961.2	ENSP00000384792.1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4967 AN: 152154 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0435 AC: 10947 AN: 251382 AF XY: 0.0450

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.0370

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0377 AC: 55110 AN: 1461864 Hom.: 1298 Cov.: 34 AF XY: 0.0387 AC XY: 28116 AN XY: 727230

African (AFR) AF: 0.0140 AC: 469 AN: 33480

American (AMR) AF: 0.0203 AC: 908 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 1740 AN: 26136

East Asian (EAS) AF: 0.104 AC: 4124 AN: 39700

South Asian (SAS) AF: 0.0612 AC: 5280 AN: 86258

European-Finnish (FIN) AF: 0.0328 AC: 1753 AN: 53392

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0341 AC: 37879 AN: 1112010

Other (OTH) AF: 0.0452 AC: 2731 AN: 60396

GnomAD4 genome AF: 0.0327 AC: 4974 AN: 152272 Hom.: 126 Cov.: 33 AF XY: 0.0328 AC XY: 2445 AN XY: 74444

African (AFR) AF: 0.0143 AC: 594 AN: 41562

American (AMR) AF: 0.0268 AC: 411 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3470

East Asian (EAS) AF: 0.111 AC: 573 AN: 5172

South Asian (SAS) AF: 0.0637 AC: 307 AN: 4822

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0358 AC: 2431 AN: 67998

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0356 Hom.: 59

Bravo AF: 0.0309

Asia WGS AF: 0.132 AC: 458 AN: 3478

EpiCase AF: 0.0378

EpiControl AF: 0.0348

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 05, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.57
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45470992; hg19: chr19-36594369; COSMIC: COSV54336952;