rs199676595

Variant names:

• chr2-63404168-C-T
• rs199676595
• NM_015910.7:c.1315G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-63404168-C-T
• chr2-63404168-C-A
• chr2-63404168-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015910.7(WDPCP):​c.1315G>A​(p.Val439Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000555 in 1,613,990 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (4 hom.)
• Consequence: WDPCP NM_015910.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.200
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004932314).
• BP6: Variant 2-63404168-C-T is Benign according to our data. Variant chr2-63404168-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188367.
• BS2: High Homozygotes in GnomAdExome4 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.1315G>A	p.Val439Ile	missense	Exon 10 of 18	NP_056994.3	O95876-1
	WDPCP	NM_001354044.2		c.1243G>A	p.Val415Ile	missense	Exon 11 of 19	NP_001340973.1
	WDPCP	NM_001354045.2		c.1315G>A	p.Val439Ile	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.1315G>A	p.Val439Ile	missense	Exon 10 of 18	ENSP00000272321.7	O95876-1
	WDPCP	ENST00000409562.7	TSL:1	c.1315G>A	p.Val439Ile	missense	Exon 10 of 14	ENSP00000387222.3	O95876-2
	WDPCP	ENST00000398544.7	TSL:1	c.838G>A	p.Val280Ile	missense	Exon 4 of 12	ENSP00000381552.3	O95876-3

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000784 AC: 195 AN: 248862 AF XY: 0.000652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000461

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000560 AC: 818 AN: 1461826 Hom.: 4 Cov.: 30 AF XY: 0.000551 AC XY: 401 AN XY: 727214

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 349 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000337 AC: 375 AN: 1111980

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74328

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68042

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.000518

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000484 AC: 4

ExAC AF: 0.000654 AC: 79

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome (1)
-	1	-	Bardet-Biedl syndrome 15 (1)
-	-	1	not provided (1)
-	-	1	WDPCP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N
PhyloP100		0.20
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.040
Sift	Benign	0.30	T
Sift4G	Benign	0.27	T
Polyphen		0.015	B
Vest4		0.026
MVP		0.55
MPC		0.10
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.028
gMVP		0.081
Mutation Taster		=99/1	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: rs199676595; hg19: chr2-63631303; COSMIC: COSV99042278;