rs12327568

chr19-36067994-A-G

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.866A>G(p.Lys289Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,613,976 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.10

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=0.008493841).
• BP6: Variant 19-36067994-A-G is Benign according to our data. Variant chr19-36067994-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 160308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36067994-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00453 (690/152332) while in subpopulation AFR AF= 0.0161 (668/41580). AF 95% confidence interval is 0.0151. There are 6 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.866A>G	p.Lys289Arg	missense_variant	7/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.866A>G	p.Lys289Arg	missense_variant	7/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 689 AN: 152214 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 250662 Hom.: 1 AF XY: 0.000878 AC XY: 119 AN XY: 135540

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.000522

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: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000467 AC: 683 AN: 1461644 Hom.: 5 Cov.: 33 AF XY: 0.000428 AC XY: 311 AN XY: 727114

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00453 AC: 690 AN: 152332 Hom.: 6 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74488

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.00509

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

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	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.073
Sift	Benign	0.082	T;T;D
Sift4G	Uncertain	0.046	D;D;T
Polyphen		0.95	P;P;.
Vest4		0.44
MVP		0.49
MPC		0.61
ClinPred		0.053	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.51

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: rs12327568; hg19: chr19-36558896;