chr19-36055113-C-T

Position:

• chr19-36055113-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000401500.7(WDR62):​c.142C>T​(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,607,278 control chromosomes in the GnomAD database, including 153 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (6 hom., cov: 33)
  • Exomes 𝑓: 0.014 (147 hom.)
• Consequence: WDR62 ENST00000401500.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.382

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=0.0042237043).
• BP6: Variant 19-36055113-C-T is Benign according to our data. Variant chr19-36055113-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36055113-C-T is described in Lovd as [Benign]. Variant chr19-36055113-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00772 (1176/152240) while in subpopulation NFE AF= 0.0137 (932/67994). AF 95% confidence interval is 0.013. There are 6 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.142C>T	p.Leu48Phe	missense_variant	1/32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.142C>T	p.Leu48Phe	missense_variant	1/32	1	NM_001083961.2	ENSP00000384792	P4

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152122 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00715 AC: 1638 AN: 229006 Hom.: 14 AF XY: 0.00735 AC XY: 930 AN XY: 126458

Gnomad AFR exome AF: 0.00274

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00156

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00657

GnomAD4 exome AF: 0.0135 AC: 19664 AN: 1455038 Hom.: 147 Cov.: 32 AF XY: 0.0132 AC XY: 9542 AN XY: 723542

Gnomad4 AFR exome AF: 0.00201

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00409

Gnomad4 FIN exome AF: 0.00267

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.00772 AC: 1176 AN: 152240 Hom.: 6 Cov.: 33 AF XY: 0.00699 AC XY: 520 AN XY: 74436

Gnomad4 AFR AF: 0.00306

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.0122 Hom.: 22

Bravo AF: 0.00789

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00326 AC: 13

ESP6500EA AF: 0.0104 AC: 83

ExAC AF: 0.00645 AC: 770

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	WDR62: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.0068	.;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	0.78	N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.17
MVP		0.61
MPC		0.24
ClinPred		0.0078	T
GERP RS		4.3
Varity_R		0.076
gMVP		0.29

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: rs62109744; hg19: chr19-36546015; COSMIC: COSV105820158; COSMIC: COSV105820158;