19-36073536-G-GC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001083961.2(WDR62):c.1233+15dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 146,408 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 31)

Exomes 𝑓: 0.019 ( 5 hom. )

Failed GnomAD Quality Control

Consequence

WDR62
NM_001083961.2 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.491

Publications

0 publications found

Variant links:

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]

WDR62 Gene-Disease associations (from GenCC):

microcephaly 2, primary, autosomal recessive, with or without cortical malformations
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P, ClinGen
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR62 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 19-36073536-G-GC is Benign according to our data. Variant chr19-36073536-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199056.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1883/146408) while in subpopulation AFR AF = 0.0304 (1202/39600). AF 95% confidence interval is 0.0289. There are 17 homozygotes in GnomAd4. There are 837 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR62	NM_001083961.2 link	c.1233+15dupC		intron_variant	Intron 9 of 31	ENST00000401500.7	NP_001077430.1	O43379-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7 link	c.1233+5_1233+6insC		splice_region_variant, intron_variant	Intron 9 of 31	1	NM_001083961.2	ENSP00000384792.1		O43379-4

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1877

AN:

146326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00668

Gnomad AMR

AF:

0.00650

Gnomad ASJ

AF:

0.00588

Gnomad EAS

AF:

0.00497

Gnomad SAS

AF:

0.00832

Gnomad FIN

AF:

0.00455

Gnomad MID

AF:

0.00658

Gnomad NFE

AF:

0.00655

Gnomad OTH

AF:

0.00844

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0187

AC:

19769

AN:

1056590

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

9694

AN XY:

532610

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0538

AC:

1360

AN:

25266

American (AMR)

AF:

0.0213

AC:

768

AN:

36008

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

266

AN:

19508

East Asian (EAS)

AF:

0.0129

AC:

391

AN:

30248

South Asian (SAS)

AF:

0.0113

AC:

848

AN:

75358

European-Finnish (FIN)

AF:

0.0104

AC:

429

AN:

41436

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

4534

European-Non Finnish (NFE)

AF:

0.0190

AC:

14799

AN:

780166

Other (OTH)

AF:

0.0191

AC:

842

AN:

44066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

Heterozygous variant carriers

2454

4908

7362

9816

12270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

654

1308

1962

2616

3270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0129

AC:

1883

AN:

146408

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

837

AN XY:

71248

show subpopulations

African (AFR)

AF:

0.0304

AC:

1202

AN:

39600

American (AMR)

AF:

0.00649

AC:

AN:

14632

Ashkenazi Jewish (ASJ)

AF:

0.00588

AC:

AN:

3404

East Asian (EAS)

AF:

0.00499

AC:

AN:

5014

South Asian (SAS)

AF:

0.00834

AC:

AN:

4556

European-Finnish (FIN)

AF:

0.00455

AC:

AN:

9880

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00655

AC:

433

AN:

66110

Other (OTH)

AF:

0.00836

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0298

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary Microcephaly 2 With or Without Cortical Malformations

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.49

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over