19-36103640-C-T

Position:

chr19-36103640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000401500.7(WDR62):c.3812C>T(p.Ala1271Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,609,386 control chromosomes in the GnomAD database, including 23 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1271T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 23 hom. )

Consequence

WDR62
ENST00000401500.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.401

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037599802).

BP6

Variant 19-36103640-C-T is Benign according to our data. Variant chr19-36103640-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36103640-C-T is described in Lovd as [Benign]. Variant chr19-36103640-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00295 (445/151088) while in subpopulation NFE AF= 0.00553 (374/67604). AF 95% confidence interval is 0.00507. There are 0 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2 linkuse as main transcript	c.3812C>T	p.Ala1271Val	missense_variant	30/32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7 linkuse as main transcript	c.3812C>T	p.Ala1271Val	missense_variant	30/32	1	NM_001083961.2	ENSP00000384792	P4	O43379-4

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

445

AN:

150968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000757

Gnomad AMI

AF:

0.00222

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.00232

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00193

GnomAD3 exomes

AF:

0.00283

AC:

704

AN:

248548

Hom.:

AF XY:

0.00276

AC XY:

371

AN XY:

134660

show subpopulations

Gnomad AFR exome

AF:

0.000618

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00201

Gnomad NFE exome

AF:

0.00510

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00450

AC:

6556

AN:

1458298

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

3201

AN XY:

725624

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00182

Gnomad4 NFE exome

AF:

0.00544

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.00295

AC:

445

AN:

151088

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

192

AN XY:

73860

show subpopulations

Gnomad4 AFR

AF:

0.000754

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00232

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00105

Gnomad4 FIN

AF:

0.00152

Gnomad4 NFE

AF:

0.00553

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.00461

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00294

AC:

357

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 13, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	WDR62: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 23, 2015	- -

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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.1

DANN

Benign

0.22

DEOGEN2

Benign

0.0029

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.025

Sift

Benign

0.75

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.31

B;B

Vest4

0.049

MVP

0.41

MPC

0.22

ClinPred

0.0023

GERP RS

-2.7

Varity_R

0.035

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over