19-36055053-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001083961.2(WDR62):c.82C>T(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,589,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.861

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1333518).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000752 (1081/1437480) while in subpopulation NFE AF= 0.000927 (1021/1101526). AF 95% confidence interval is 0.000879. There are 1 homozygotes in gnomad4_exome. There are 492 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.82C>T	p.Arg28Trp	missense_variant	1/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.82C>T	p.Arg28Trp	missense_variant	1/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000426 AC: 85 AN: 199616 Hom.: 0 AF XY: 0.000436 AC XY: 48 AN XY: 110062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000898

Gnomad OTH exome AF: 0.000586

GnomAD4 exome AF: 0.000752 AC: 1081 AN: 1437480 Hom.: 1 Cov.: 31 AF XY: 0.000689 AC XY: 492 AN XY: 713680

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000231

Gnomad4 NFE exome AF: 0.000927

Gnomad4 OTH exome AF: 0.000691

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.000337 AC XY: 25 AN XY: 74284

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000370

ExAC AF: 0.000490 AC: 58

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2023	- -

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 07, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	0.027	D
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	0.77	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.67
MVP		0.84
MPC		0.84
ClinPred		0.15	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.46

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: rs200283315; hg19: chr19-36545955;