1-112509314-G-A

Position:

• chr1-112509314-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024494.3(WNT2B):​c.52G>A​(p.Ala18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,415,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: WNT2B NM_024494.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.223

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036995947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT2B	NM_024494.3	c.52G>A	p.Ala18Thr	missense_variant	1/5	ENST00000369684.5
WNT2B	NM_001291880.1	c.-94-5560G>A		intron_variant
WNT2B	NM_004185.4	c.126-5560G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT2B	ENST00000369684.5	c.52G>A	p.Ala18Thr	missense_variant	1/5	1	NM_024494.3	P1
WNT2B	ENST00000369686.9	c.126-5560G>A		intron_variant		1
WNT2B	ENST00000256640.9	c.-94-5560G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000394 AC: 7 AN: 177448 Hom.: 0 AF XY: 0.0000303 AC XY: 3 AN XY: 98872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000512

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1415876 Hom.: 0 Cov.: 33 AF XY: 0.0000142 AC XY: 10 AN XY: 702408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000557

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000756

ExAC AF: 0.0000265 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.52G>A (p.A18T) alteration is located in exon 1 (coding exon 1) of the WNT2B gene. This alteration results from a G to A substitution at nucleotide position 52, causing the alanine (A) at amino acid position 18 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the WNT2B protein (p.Ala18Thr). This variant is present in population databases (rs3828075, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with WNT2B-related conditions. 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 threonine 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.10
Sift	Benign	0.33	T
Sift4G	Uncertain	0.042	D
Polyphen		0.20	B
Vest4		0.10
MutPred		0.12		Gain of glycosylation at A18 (P = 0.0065);
MVP		0.53
MPC		1.0
ClinPred		0.15	T
GERP RS		2.0
Varity_R		0.032
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs3828075; hg19: chr1-113051936;