rs189817127

chr2-63404220-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_015910.7(WDPCP):c.1263A>C(p.Leu421Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.923

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011816651).
• BP6: Variant 2-63404220-T-G is Benign according to our data. Variant chr2-63404220-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 462949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00131 (200/152270) while in subpopulation AFR AF= 0.0045 (187/41554). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDPCP	NM_015910.7	c.1263A>C	p.Leu421Phe	missense_variant	10/18	ENST00000272321.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDPCP	ENST00000272321.12	c.1263A>C	p.Leu421Phe	missense_variant	10/18	1	NM_015910.7	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000350 AC: 87 AN: 248426 Hom.: 0 AF XY: 0.000319 AC XY: 43 AN XY: 134708

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000159 AC: 232 AN: 1461516 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 726998

Gnomad4 AFR exome AF: 0.00400

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74456

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.00140

ESP6500AA AF: 0.00260 AC: 10

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000372 AC: 45

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0037	T;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;.;L
MutationTaster	Benign	0.91	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.41	B;B;B;B;P
Vest4		0.052
MutPred		0.19		Loss of stability (P = 0.0821);.;.;.;Loss of stability (P = 0.0821);
MVP		0.51
MPC		0.42
ClinPred		0.0061	T
GERP RS		3.0
Varity_R		0.058
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs189817127; hg19: chr2-63631355;