dbSNP rs45567532: WDR62:p.Asp490Glu (chr19-36083161-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001083961.2(WDR62):c.1470C>G(p.Asp490Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D490D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

WDR62
NM_001083961.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.840

Publications

8 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 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001083961.2

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083961.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR62	NM_001083961.2	MANE Select	c.1470C>G	p.Asp490Glu	missense	Exon 11 of 32	NP_001077430.1
WDR62	NM_001411145.1		c.1455C>G	p.Asp485Glu	missense	Exon 11 of 32	NP_001398074.1
WDR62	NM_173636.5		c.1470C>G	p.Asp490Glu	missense	Exon 11 of 32	NP_775907.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR62	ENST00000401500.7	TSL:1 MANE Select	c.1470C>G	p.Asp490Glu	missense	Exon 11 of 32	ENSP00000384792.1
WDR62	ENST00000587391.6	TSL:1	n.*160C>G		non_coding_transcript_exon	Exon 12 of 30	ENSP00000465525.1
WDR62	ENST00000587391.6	TSL:1	n.*160C>G		3_prime_UTR	Exon 12 of 30	ENSP00000465525.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

540

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.079

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.69

M_CAP

Benign

0.031

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.2

PhyloP100

-0.84

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.16

Sift

Benign

0.038

Sift4G

Uncertain

0.054

Polyphen

1.0

Vest4

0.10

MutPred

0.35

Loss of sheet (P = 0.0817)

MVP

0.50

MPC

0.36

ClinPred

0.85

GERP RS

-9.1

Varity_R

0.15

gMVP

0.65

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over