chr2-63588204-G-T

Variant names:

• chr2-63588204-G-T
• rs141340867
• NM_015910.7:c.68C>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.68C>A​(p.Pro23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,568,786 control chromosomes in the GnomAD database, including 6 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P23A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.47
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028963685).
• BP6: Variant 2-63588204-G-T is Benign according to our data. Variant chr2-63588204-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193388.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 = 0.00374 (570/152318) while in subpopulation AFR AF = 0.0128 (531/41576). AF 95% confidence interval is 0.0119. There are 4 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.68C>A	p.Pro23Gln	missense	Exon 1 of 18	NP_056994.3	O95876-1
	WDPCP	NM_001354045.2		c.68C>A	p.Pro23Gln	missense	Exon 1 of 13	NP_001340974.1
	WDPCP	NM_001354044.2		c.-257C>A		5_prime_UTR	Exon 1 of 19	NP_001340973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDPCP	ENST00000272321.12	TSL:1 MANE Select	c.68C>A	p.Pro23Gln	missense	Exon 1 of 18	ENSP00000272321.7	O95876-1
	WDPCP	ENST00000409562.7	TSL:1	c.68C>A	p.Pro23Gln	missense	Exon 1 of 14	ENSP00000387222.3	O95876-2
	WDPCP	ENST00000409835.5	TSL:1	n.315C>A		non_coding_transcript_exon	Exon 1 of 13

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152200 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000766 AC: 138 AN: 180074 AF XY: 0.000631

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000573

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.000632

GnomAD4 exome AF: 0.000402 AC: 569 AN: 1416468 Hom.: 2 Cov.: 31 AF XY: 0.000348 AC XY: 244 AN XY: 700394

African (AFR) AF: 0.0145 AC: 462 AN: 31942

American (AMR) AF: 0.000716 AC: 29 AN: 40530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 36666

South Asian (SAS) AF: 0.0000371 AC: 3 AN: 80906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50196

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5726

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1086598

Other (OTH) AF: 0.000975 AC: 57 AN: 58464

GnomAD4 genome AF: 0.00374 AC: 570 AN: 152318 Hom.: 4 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74490

African (AFR) AF: 0.0128 AC: 531 AN: 41576

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00154 Hom.: 2

Bravo AF: 0.00427

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00930 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000812 AC: 96

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.61
DANN	Benign	0.71
DEOGEN2	Benign	0.00058	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.12
Sift	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.069
MVP		0.21
MPC		0.10
ClinPred		0.0035	T
GERP RS		-3.5
PromoterAI		0.0022	Neutral
Varity_R		0.031
gMVP		0.24
Mutation Taster		=100/0	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: rs141340867; hg19: chr2-63815338;