rs200322968

Variant names:

• chr2-63492856-C-G
• rs200322968
• NM_015910.7:c.160G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-63492856-C-G
• chr2-63492856-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_015910.7(WDPCP):​c.160G>C​(p.Asp54His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D54N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WDPCP NM_015910.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69
• Publications: 7 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• heart defect - tongue hamartoma - polysyndactyly syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-63492856-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162669.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDPCP	NM_015910.7	c.160G>C	p.Asp54His	missense_variant, splice_region_variant	Exon 2 of 18	ENST00000272321.12	NP_056994.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDPCP	ENST00000272321.12	c.160G>C	p.Asp54His	missense_variant, splice_region_variant	Exon 2 of 18	1	NM_015910.7	ENSP00000272321.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0060	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.89	P;D;.
Vest4		0.85
MutPred		0.58		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.91
MPC		0.58
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.61
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200322968; hg19: chr2-63719990;