dbSNP rs202196322: WDPCP:p.Ile59Asn (chr2-63487479-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015910.7(WDPCP):c.176T>A(p.Ile59Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,596,126 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 9 hom. )

Consequence

WDPCP
NM_015910.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 3.64

Publications

4 publications found

Variant links:

Genes affected

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WDPCP Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 15
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
heart defect - tongue hamartoma - polysyndactyly syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

WDPCP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019254684).

BP6

Variant 2-63487479-A-T is Benign according to our data. Variant chr2-63487479-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220911.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00152 (232/152132) while in subpopulation NFE AF = 0.00278 (189/67964). AF 95% confidence interval is 0.00246. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015910.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WDPCP	NM_015910.7	MANE Select	c.176T>A	p.Ile59Asn	missense	Exon 3 of 18	NP_056994.3	O95876-1
WDPCP	NM_001354044.2		c.104T>A	p.Ile35Asn	missense	Exon 4 of 19	NP_001340973.1
WDPCP	NM_001354045.2		c.176T>A	p.Ile59Asn	missense	Exon 3 of 13	NP_001340974.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WDPCP	ENST00000272321.12	TSL:1 MANE Select	c.176T>A	p.Ile59Asn	missense	Exon 3 of 18	ENSP00000272321.7	O95876-1
WDPCP	ENST00000409562.7	TSL:1	c.176T>A	p.Ile59Asn	missense	Exon 3 of 14	ENSP00000387222.3	O95876-2
WDPCP	ENST00000409835.5	TSL:1	n.423T>A		non_coding_transcript_exon	Exon 3 of 13

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

232

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000788

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00136

AC:

338

AN:

248120

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.000760

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00258

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00224

AC:

3240

AN:

1443994

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1559

AN XY:

719468

show subpopulations

African (AFR)

AF:

0.000424

AC:

AN:

33010

American (AMR)

AF:

0.000787

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39486

South Asian (SAS)

AF:

0.000245

AC:

AN:

85748

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.00280

AC:

3068

AN:

1096924

Other (OTH)

AF:

0.00158

AC:

AN:

59638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

130

260

389

519

649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.00152

AC:

232

AN:

152132

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41526

American (AMR)

AF:

0.000786

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00278

AC:

189

AN:

67964

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00208

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00247

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.00263

EpiControl

AF:

0.00220

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Bardet-Biedl syndrome (1)

Bardet-Biedl syndrome 15 (1)

Heart defect - tongue hamartoma - polysyndactyly syndrome;C3150127:Bardet-Biedl syndrome 15 (1)

WDPCP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.057

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

PhyloP100

3.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

REVEL

Benign

0.25

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0060

Polyphen

0.63

Vest4

0.86

MVP

0.78

MPC

0.37

ClinPred

0.031

GERP RS

3.1

Varity_R

0.33

gMVP

0.39

Mutation Taster

=90/10

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