rs774995085

chr2-63433783-TGGCTCTGTCCTTCTCAGAAGAAATGGG-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BP6

The NM_015910.7(WDPCP):c.760_786del(p.Pro254_Ala262del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000431 in 1,613,558 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: WDPCP NM_015910.7 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_015910.7.
• BP6: Variant 2-63433783-TGGCTCTGTCCTTCTCAGAAGAAATGGG-T is Benign according to our data. Variant chr2-63433783-TGGCTCTGTCCTTCTCAGAAGAAATGGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531819.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDPCP	NM_015910.7	c.760_786del	p.Pro254_Ala262del	inframe_deletion	9/18	ENST00000272321.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDPCP	ENST00000272321.12	c.760_786del	p.Pro254_Ala262del	inframe_deletion	9/18	1	NM_015910.7	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 74 AN: 248902 Hom.: 0 AF XY: 0.000267 AC XY: 36 AN XY: 135032

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000638

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000441 AC: 645 AN: 1461344 Hom.: 2 AF XY: 0.000417 AC XY: 303 AN XY: 726920

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74358

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

WDPCP-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

The WDPCP c.760_786del27 variant is predicted to result in an in-frame deletion (p.Pro254_Ala262del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

This variant, c.760_786del, results in the deletion of 9 amino acid(s) of the WDPCP protein (p.Pro254_Ala262del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774995085, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with WDPCP-related conditions. ClinVar contains an entry for this variant (Variation ID: 531819). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs774995085; hg19: chr2-63660917;