rs61734466

Variant names:

• chr2-63404150-C-G
• rs61734466
• NM_015910.7:c.1333G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-63404150-C-G
• chr2-63404150-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015910.7(WDPCP):​c.1333G>C​(p.Ala445Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00758 in 1,614,098 control chromosomes in the GnomAD database, including 61 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 0.0055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (59 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.50
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008161902).
• BP6: Variant 2-63404150-C-G is Benign according to our data. Variant chr2-63404150-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00551 (839/152288) while in subpopulation NFE AF = 0.00972 (661/68022). AF 95% confidence interval is 0.0091. There are 2 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1333G>C	p.Ala445Pro	missense	Exon 10 of 18	NP_056994.3	O95876-1
	WDPCP	NM_001354044.2		c.1261G>C	p.Ala421Pro	missense	Exon 11 of 19	NP_001340973.1
	WDPCP	NM_001354045.2		c.1333G>C	p.Ala445Pro	missense	Exon 10 of 13	NP_001340974.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDPCP	ENST00000272321.12	TSL:1 MANE Select	c.1333G>C	p.Ala445Pro	missense	Exon 10 of 18	ENSP00000272321.7	O95876-1
	WDPCP	ENST00000409562.7	TSL:1	c.1333G>C	p.Ala445Pro	missense	Exon 10 of 14	ENSP00000387222.3	O95876-2
	WDPCP	ENST00000398544.7	TSL:1	c.856G>C	p.Ala286Pro	missense	Exon 4 of 12	ENSP00000381552.3	O95876-3

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 840 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00565 AC: 1407 AN: 248940 AF XY: 0.00578

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00779 AC: 11391 AN: 1461810 Hom.: 59 Cov.: 30 AF XY: 0.00752 AC XY: 5472 AN XY: 727208

African (AFR) AF: 0.00143 AC: 48 AN: 33476

American (AMR) AF: 0.00139 AC: 62 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86250

European-Finnish (FIN) AF: 0.00350 AC: 187 AN: 53420

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5762

European-Non Finnish (NFE) AF: 0.00955 AC: 10623 AN: 1111972

Other (OTH) AF: 0.00619 AC: 374 AN: 60394

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00498 AC XY: 371 AN XY: 74468

African (AFR) AF: 0.00188 AC: 78 AN: 41566

American (AMR) AF: 0.00327 AC: 50 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00972 AC: 661 AN: 68022

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00753 Hom.: 7

Bravo AF: 0.00499

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00157 AC: 6

ESP6500EA AF: 0.00980 AC: 81

ExAC AF: 0.00660 AC: 797

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00786

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.0044
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.088
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.076	B
Vest4		0.48
MVP		0.55
MPC		0.61
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.41
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61734466; hg19: chr2-63631285;