1-112509273-C-T

Variant names:

• chr1-112509273-C-T
• rs1314920760
• NM_024494.3:c.11C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024494.3(WNT2B):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,379,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WNT2B NM_024494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0870
• Publications: 0 publications found

Genes affected

WNT2B (HGNC:12781): (Wnt family member 2B) This gene encodes a member of the wingless-type MMTV integration site (WNT) family of highly conserved, secreted signaling factors. WNT family members function in a variety of developmental processes including regulation of cell growth and differentiation and are characterized by a WNT-core domain. This gene may play a role in human development as well as carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WNT2B Gene-Disease associations (from GenCC):

• diarrhea 9

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18202001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT2B	NM_024494.3	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 5	ENST00000369684.5	NP_078613.1
WNT2B	NM_004185.4	c.126-5601C>T		intron_variant	Intron 2 of 5		NP_004176.2
WNT2B	NM_001291880.1	c.-94-5601C>T		intron_variant	Intron 1 of 4		NP_001278809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT2B	ENST00000369684.5	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 5	1	NM_024494.3	ENSP00000358698.4
WNT2B	ENST00000369686.9	c.126-5601C>T		intron_variant	Intron 2 of 5	1		ENSP00000358700.4
WNT2B	ENST00000256640.9	c.-94-5601C>T		intron_variant	Intron 1 of 4	2		ENSP00000256640.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000773 AC: 1 AN: 129402 AF XY: 0.0000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379818 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 681856

African (AFR) AF: 0.00 AC: 0 AN: 29674

American (AMR) AF: 0.00 AC: 0 AN: 33888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24310

East Asian (EAS) AF: 0.00 AC: 0 AN: 34716

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076698

Other (OTH) AF: 0.00 AC: 0 AN: 57296

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with WNT2B-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the WNT2B protein (p.Pro4Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.087
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.36	B
Vest4		0.21
MutPred		0.18		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.84
MPC		1.3
ClinPred		0.54	D
GERP RS		3.0
PromoterAI		0.043	Neutral
Varity_R		0.037
gMVP		0.44
Mutation Taster		=91/9	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: rs1314920760; hg19: chr1-113051895;