chr17-75848667-A-G

Position:

• chr17-75848667-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012478.4(WBP2):​c.305-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,610,644 control chromosomes in the GnomAD database, including 103,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (19950 hom., cov: 33)
  • Exomes 𝑓: 0.32 (83235 hom.)
• Consequence: WBP2 NM_012478.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004055
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46

Genes affected

WBP2 (HGNC:12738): (WW domain binding protein 2) The globular WW domain is composed of 38 to 40 semiconserved amino acids shared by proteins of diverse functions including structural, regulatory, and signaling proteins. The domain is involved in mediating protein-protein interactions through the binding of polyproline ligands. This gene encodes a WW domain binding protein that is a transcriptional coactivator of estrogen receptor alpha and progesterone receptor. Defects in this gene have been associated with hearing impairment. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-75848667-A-G is Benign according to our data. Variant chr17-75848667-A-G is described in ClinVar as [Benign]. Clinvar id is 1264383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WBP2	NM_012478.4	c.305-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000254806.8	NP_036610.2
WBP2	NM_001330499.2	c.305-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001317428.1
WBP2	NM_001348170.1	c.305-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001335099.1
WBP2	XM_047435712.1	c.239-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047291668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WBP2	ENST00000254806.8	c.305-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012478.4	ENSP00000254806	P4

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68700 AN: 151972 Hom.: 19889 Cov.: 33

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.332 AC: 82186 AN: 247894 Hom.: 16315 AF XY: 0.329 AC XY: 44145 AN XY: 134024

Gnomad AFR exome AF: 0.844

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.324 AC: 473019 AN: 1458554 Hom.: 83235 Cov.: 32 AF XY: 0.325 AC XY: 235674 AN XY: 725560

Gnomad4 AFR exome AF: 0.850

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.353

GnomAD4 genome AF: 0.452 AC: 68820 AN: 152090 Hom.: 19950 Cov.: 33 AF XY: 0.442 AC XY: 32893 AN XY: 74336

Gnomad4 AFR AF: 0.828

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.449

Alfa AF: 0.352 Hom.: 7544

Bravo AF: 0.478

Asia WGS AF: 0.315 AC: 1096 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hearing loss, autosomal recessive 107 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs2290771; hg19: chr17-73844748; COSMIC: COSV52884819; COSMIC: COSV52884819;