2-63122011-C-G

Variant names:

• chr2-63122011-C-G
• rs1669574589
• NM_015910.7:c.2236G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015910.7(WDPCP):​c.2236G>C​(p.Val746Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46
• Publications: 0 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: 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

ENSG00000286480 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22025701).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDPCP	NM_015910.7	MANE Select	c.2236G>C	p.Val746Leu	missense	Exon 18 of 18	NP_056994.3	O95876-1
	WDPCP	NM_001354044.2		c.2164G>C	p.Val722Leu	missense	Exon 19 of 19	NP_001340973.1
	WDPCP	NM_001042692.3		c.1759G>C	p.Val587Leu	missense	Exon 12 of 12	NP_001036157.1	O95876-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDPCP	ENST00000272321.12	TSL:1 MANE Select	c.2236G>C	p.Val746Leu	missense	Exon 18 of 18	ENSP00000272321.7	O95876-1
	WDPCP	ENST00000398544.7	TSL:1	c.1759G>C	p.Val587Leu	missense	Exon 12 of 12	ENSP00000381552.3	O95876-3
	WDPCP	ENST00000409120.5	TSL:1	c.1660G>C	p.Val554Leu	missense	Exon 12 of 12	ENSP00000386769.1	E9PFG9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461184 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111686

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.63	T
PhyloP100		3.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.35	B
Vest4		0.24
MutPred		0.32		Gain of disorder (P = 0.0459)
MVP		0.78
MPC		0.11
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.32
gMVP		0.22
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1669574589; hg19: chr2-63349146;