chr19-36101683-C-T

Variant names:

• chr19-36101683-C-T
• rs77898819
• NM_001083961.2:c.2991C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083961.2(WDR62):​c.2991C>T​(p.Ala997Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,550,910 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (140 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-36101683-C-T is Benign according to our data. Variant chr19-36101683-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36101683-C-T is described in Lovd as [Benign]. Variant chr19-36101683-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0105 (1593/152252) while in subpopulation SAS AF= 0.0418 (201/4814). AF 95% confidence interval is 0.037. There are 12 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.2991C>T	p.Ala997Ala	synonymous_variant	Exon 25 of 32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.2991C>T	p.Ala997Ala	synonymous_variant	Exon 25 of 32	1	NM_001083961.2	ENSP00000384792.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1594 AN: 152134 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0120 AC: 1860 AN: 154824 Hom.: 29 AF XY: 0.0141 AC XY: 1154 AN XY: 81870

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00514

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00862 AC: 12054 AN: 1398658 Hom.: 140 Cov.: 32 AF XY: 0.00964 AC XY: 6650 AN XY: 689864

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0402

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 152252 Hom.: 12 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74436

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0418

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00750 Hom.: 1

Bravo AF: 0.0105

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Nov 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.2
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs77898819; hg19: chr19-36592585;