Genetic Variant WDR62:p.Leu48Phe (chr19-36055113-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001083961.2(WDR62):c.142C>T(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,607,278 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 6 hom., cov: 33)

Exomes 𝑓: 0.014 ( 147 hom. )

Consequence

WDR62
NM_001083961.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.382

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042237043).

BP6

Variant 19-36055113-C-T is Benign according to our data. Variant chr19-36055113-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1176/152240) while in subpopulation NFE AF = 0.0137 (932/67994). AF 95% confidence interval is 0.013. There are 6 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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.142C>T	p.Leu48Phe	missense	Exon 1 of 32	NP_001077430.1
WDR62	NM_001411145.1		c.142C>T	p.Leu48Phe	missense	Exon 1 of 32	NP_001398074.1
WDR62	NM_173636.5		c.142C>T	p.Leu48Phe	missense	Exon 1 of 32	NP_775907.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR62	ENST00000401500.7	TSL:1 MANE Select	c.142C>T	p.Leu48Phe	missense	Exon 1 of 32	ENSP00000384792.1
WDR62	ENST00000587391.6	TSL:1	n.142C>T		non_coding_transcript_exon	Exon 1 of 30	ENSP00000465525.1
WDR62	ENST00000679714.1		c.142C>T	p.Leu48Phe	missense	Exon 1 of 32	ENSP00000506627.1

Frequencies

GnomAD3 genomes

AF:

0.00773

AC:

1176

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00715

AC:

1638

AN:

229006

AF XY:

0.00735

show subpopulations

Gnomad AFR exome

AF:

0.00274

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00232

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00657

GnomAD4 exome

AF:

0.0135

AC:

19664

AN:

1455038

Hom.:

147

Cov.:

AF XY:

0.0132

AC XY:

9542

AN XY:

723542

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

33324

American (AMR)

AF:

0.00232

AC:

103

AN:

44324

Ashkenazi Jewish (ASJ)

AF:

0.00212

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00409

AC:

349

AN:

85398

European-Finnish (FIN)

AF:

0.00267

AC:

136

AN:

50922

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0166

AC:

18387

AN:

1109898

Other (OTH)

AF:

0.00936

AC:

562

AN:

60050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1138

2275

3413

4550

5688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

720

1440

2160

2880

3600

<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:

0.00772

AC:

1176

AN:

152240

Hom.:

Cov.:

AF XY:

0.00699

AC XY:

520

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00306

AC:

127

AN:

41554

American (AMR)

AF:

0.00379

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00290

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0137

AC:

932

AN:

67994

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

Hom.:

Bravo

AF:

0.00789

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00326

AC:

ESP6500EA

AF:

0.0104

AC:

ExAC

AF:

0.00645

AC:

770

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (4)

not specified (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

PhyloP100

0.38

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Benign

0.34

Sift4G

Benign

0.72

Polyphen

0.0030

Vest4

0.17

MVP

0.61

MPC

0.24

ClinPred

0.0078

GERP RS

4.3

PromoterAI

0.067

Neutral

(source)

Varity_R

0.076

gMVP

0.29

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over