rs144697999

Positions:

• chr19-36099407-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001083961.2(WDR62):​c.2529C>T​(p.Asp843=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,613,460 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (3 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.966

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-36099407-C-T is Benign according to our data. Variant chr19-36099407-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160268.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.966 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000615 (899/1461156) while in subpopulation MID AF= 0.00763 (43/5634). AF 95% confidence interval is 0.00582. There are 3 homozygotes in gnomad4_exome. There are 448 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.2529C>T	p.Asp843=	synonymous_variant	22/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.2529C>T	p.Asp843=	synonymous_variant	22/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00105 AC: 259 AN: 247600 Hom.: 1 AF XY: 0.000997 AC XY: 134 AN XY: 134438

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.000652

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000615 AC: 899 AN: 1461156 Hom.: 3 Cov.: 31 AF XY: 0.000616 AC XY: 448 AN XY: 726890

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000812

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000933

EpiCase AF: 0.00109

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	WDR62: BP4, BP7 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2016	- -

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.3
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144697999; hg19: chr19-36590309; COSMIC: COSV54335070;