NM_024494.3:c.73C>A

Variant names:

• chr1-112509335-C-A
• rs374417605
• NM_024494.3:c.73C>A

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.73C>A​(p.Pro25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000547 in 1,589,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: WNT2B NM_024494.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.386
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.080746055).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024494.3. 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
	WNT2B	NM_024494.3	MANE Select	c.73C>A	p.Pro25Thr	missense	Exon 1 of 5	NP_078613.1	Q93097-1
	WNT2B	NM_004185.4		c.126-5539C>A		intron	N/A	NP_004176.2	Q93097-2
	WNT2B	NM_001291880.1		c.-94-5539C>A		intron	N/A	NP_001278809.1	Q93097

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT2B	ENST00000369684.5	TSL:1 MANE Select	c.73C>A	p.Pro25Thr	missense	Exon 1 of 5	ENSP00000358698.4	Q93097-1
	WNT2B	ENST00000369686.9	TSL:1	c.126-5539C>A		intron	N/A	ENSP00000358700.4	Q93097-2
	WNT2B	ENST00000870348.1		c.73C>A	p.Pro25Thr	missense	Exon 1 of 5	ENSP00000540407.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000337 AC: 7 AN: 207832 AF XY: 0.0000604

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: 0.0000752

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000585 AC: 84 AN: 1436966 Hom.: 0 Cov.: 32 AF XY: 0.0000644 AC XY: 46 AN XY: 714808

African (AFR) AF: 0.0000315 AC: 1 AN: 31762

American (AMR) AF: 0.00 AC: 0 AN: 42912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38450

South Asian (SAS) AF: 0.00 AC: 0 AN: 84528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43462

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4140

European-Non Finnish (NFE) AF: 0.0000696 AC: 77 AN: 1106554

Other (OTH) AF: 0.0000840 AC: 5 AN: 59546

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000505 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.0
DANN	Benign	0.51
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.39
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.11
Sift	Benign	0.52	T
Sift4G	Benign	0.42	T
Polyphen		0.21	B
Vest4		0.16
MVP		0.45
MPC		0.66
ClinPred		0.024	T
GERP RS		-0.029
PromoterAI		0.39	Neutral
Varity_R		0.051
gMVP		0.54
Mutation Taster		=97/3	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: rs374417605; hg19: chr1-113051957;