19-36103640-C-T

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.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 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.401

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=0.0037599802).
• 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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.3812C>T	p.Ala1271Val	missense_variant	30/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.3812C>T	p.Ala1271Val	missense_variant	30/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 445 AN: 150968 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00276 AC XY: 371 AN XY: 134660

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.: 23 Cov.: 34 AF XY: 0.00441 AC XY: 3201 AN XY: 725624

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.: 0 Cov.: 33 AF XY: 0.00260 AC XY: 192 AN XY: 73860

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.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 13, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WDR62: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	Genetic Services Laboratory, University of Chicago	Jun 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 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	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.1
Dann	Benign	0.22
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs111294536; hg19: chr19-36594542; COSMIC: COSV54334065;