2-63174685-T-C

Variant names:

• chr2-63174685-T-C
• rs61734468
• NM_015910.7:c.2063A>G

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.2063A>G​(p.Asn688Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,868 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (8 hom., cov: 32)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.142
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037649274).
• BP6: Variant 2-63174685-T-C is Benign according to our data. Variant chr2-63174685-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220870.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 = 0.00894 (1362/152298) while in subpopulation NFE AF = 0.0151 (1029/68018). AF 95% confidence interval is 0.0144. There are 8 homozygotes in GnomAd4. There are 624 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.2063A>G	p.Asn688Ser	missense	Exon 15 of 18	NP_056994.3	O95876-1
	WDPCP	NM_001354044.2		c.1991A>G	p.Asn664Ser	missense	Exon 16 of 19	NP_001340973.1
	WDPCP	NM_001042692.3		c.1586A>G	p.Asn529Ser	missense	Exon 9 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.2063A>G	p.Asn688Ser	missense	Exon 15 of 18	ENSP00000272321.7	O95876-1
	WDPCP	ENST00000398544.7	TSL:1	c.1586A>G	p.Asn529Ser	missense	Exon 9 of 12	ENSP00000381552.3	O95876-3
	WDPCP	ENST00000409120.5	TSL:1	c.1487A>G	p.Asn496Ser	missense	Exon 9 of 12	ENSP00000386769.1	E9PFG9

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1361 AN: 152180 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00942 AC: 2348 AN: 249322 AF XY: 0.0100

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00417

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0130 AC: 18952 AN: 1461570 Hom.: 151 Cov.: 31 AF XY: 0.0130 AC XY: 9475 AN XY: 727088

African (AFR) AF: 0.00176 AC: 59 AN: 33462

American (AMR) AF: 0.00394 AC: 176 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 188 AN: 26122

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39668

South Asian (SAS) AF: 0.0133 AC: 1145 AN: 86246

European-Finnish (FIN) AF: 0.00479 AC: 256 AN: 53412

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5762

European-Non Finnish (NFE) AF: 0.0148 AC: 16494 AN: 1111800

Other (OTH) AF: 0.00976 AC: 589 AN: 60378

GnomAD4 genome AF: 0.00894 AC: 1362 AN: 152298 Hom.: 8 Cov.: 32 AF XY: 0.00838 AC XY: 624 AN XY: 74472

African (AFR) AF: 0.00267 AC: 111 AN: 41580

American (AMR) AF: 0.00497 AC: 76 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3464

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4822

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1029 AN: 68018

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0121 Hom.: 37

Bravo AF: 0.00829

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00325 AC: 12

ESP6500EA AF: 0.0169 AC: 138

ExAC AF: 0.00991 AC: 1197

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.8
DANN	Benign	0.85
DEOGEN2	Benign	0.00074	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.14
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.061
Sift	Benign	0.058	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.072
MVP		0.59
MPC		0.088
ClinPred		0.0010	T
GERP RS		2.8
Varity_R		0.049
gMVP		0.065
Mutation Taster		=100/0	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: rs61734468; hg19: chr2-63401820; COSMIC: COSV99707508;