Genetic Variant WDR62:c.1233+14_1233+15delCC (chr19-36073536-GCC-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083961.2(WDR62):c.1233+14_1233+15delCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000537 in 1,304,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

WDR62
NM_001083961.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR62	NM_001083961.2 link	c.1233+14_1233+15delCC		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+6_1233+7delCC		splice_region_variant, intron_variant	Intron 9 of 31	1	NM_001083961.2	ENSP00000384792.1		O43379-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146610

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000518

AC:

AN:

1157876

Hom.:

AF XY:

0.00000687

AC XY:

AN XY:

581978

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27550

American (AMR)

AF:

0.00

AC:

AN:

40120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21432

East Asian (EAS)

AF:

0.00

AC:

AN:

32236

South Asian (SAS)

AF:

0.00

AC:

AN:

79266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4870

European-Non Finnish (NFE)

AF:

0.00000697

AC:

AN:

860826

Other (OTH)

AF:

0.00

AC:

AN:

48032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.076331), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000682

AC:

AN:

146690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71364

show subpopulations

African (AFR)

AF:

0.0000252

AC:

AN:

39672

American (AMR)

AF:

0.00

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5020

South Asian (SAS)

AF:

0.00

AC:

AN:

4562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66234

Other (OTH)

AF:

0.00

AC:

AN:

2038

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over