NM_018639.5:c.659C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018639.5(WSB2):c.659C>T(p.Ser220Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000062 in 1,612,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S220S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

WSB2
NM_018639.5 missense, splice_region

Scores

Splicing: ADA: 0.9853

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

Publications

3 publications found

Variant links:

Genes affected

WSB2 (HGNC:19222): (WD repeat and SOCS box containing 2) This gene encodes a member of the WD-protein subfamily. The encoded protein contains five WD-repeats spanning most of the protein and an SOCS box in the C-terminus. The SOCS box may act as a bridge between specific substrate-binding domains and E3 ubiquitin protein ligases. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

WSB2 links:

RFC5 (HGNC:9973): (replication factor C subunit 5) This gene encodes the smallest subunit of the replication factor C complex, which consists of five distinct subunits (140, 40, 38, 37, and 36 kDa) and is required for DNA replication. This subunit interacts with the C-terminal region of proliferating cell nuclear antigen and is required to open and load proliferating cell nuclear antigen onto DNA during S phase. It is a member of the AAA+ (ATPases associated with various cellular activities) ATPase family and forms a core complex with the 38 and 40 kDa subunits that possesses DNA-dependent ATPase activity. A related pseudogene has been identified on chromosome 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

RFC5 links:

ENSG00000276292 (HGNC:):

ENSG00000276292 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018639.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WSB2	NM_018639.5	MANE Select	c.659C>T	p.Ser220Leu	missense splice_region	Exon 5 of 9	NP_061109.1	Q9NYS7-1
WSB2	NM_001278557.1		c.710C>T	p.Ser237Leu	missense splice_region	Exon 5 of 9	NP_001265486.1	Q9NYS7-2
WSB2	NM_001278558.2		c.29C>T	p.Ser10Leu	missense splice_region	Exon 3 of 7	NP_001265487.1	Q9NYS7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WSB2	ENST00000315436.8	TSL:1 MANE Select	c.659C>T	p.Ser220Leu	missense splice_region	Exon 5 of 9	ENSP00000319474.3	Q9NYS7-1
WSB2	ENST00000535496.5	TSL:1	c.665C>T	p.Ser222Leu	missense splice_region	Exon 4 of 8	ENSP00000439450.1	F5H280
WSB2	ENST00000540129.5	TSL:1	n.700C>T		splice_region non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250030

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726646

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111628

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

M_CAP

Benign

0.033

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PhyloP100

4.2

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.22

Sift

Benign

0.059

Sift4G

Benign

0.43

Polyphen

0.72

Vest4

0.34

MutPred

0.60

Gain of catalytic residue at S225 (P = 0)

MVP

0.40

MPC

0.55

ClinPred

0.32

GERP RS

5.2

Varity_R

0.18

gMVP

0.62

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.76

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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