NM_024494.3:c.65T>C

Variant names:

• chr1-112509327-T-C
• rs751855283
• NM_024494.3:c.65T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024494.3(WNT2B):​c.65T>C​(p.Val22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,585,296 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 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: WNT2B NM_024494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.753
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06496909).

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.65T>C	p.Val22Ala	missense	Exon 1 of 5	NP_078613.1	Q93097-1
	WNT2B	NM_004185.4		c.126-5547T>C		intron	N/A	NP_004176.2	Q93097-2
	WNT2B	NM_001291880.1		c.-94-5547T>C		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.65T>C	p.Val22Ala	missense	Exon 1 of 5	ENSP00000358698.4	Q93097-1
	WNT2B	ENST00000369686.9	TSL:1	c.126-5547T>C		intron	N/A	ENSP00000358700.4	Q93097-2
	WNT2B	ENST00000870348.1		c.65T>C	p.Val22Ala	missense	Exon 1 of 5	ENSP00000540407.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151904 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000496 AC: 1 AN: 201816 AF XY: 0.00

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: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1433392 Hom.: 0 Cov.: 32 AF XY: 0.00000982 AC XY: 7 AN XY: 712730

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.00 AC: 0 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 38326

South Asian (SAS) AF: 0.00 AC: 0 AN: 84196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1104676

Other (OTH) AF: 0.00 AC: 0 AN: 59398

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151904 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74192

African (AFR) AF: 0.0000242 AC: 1 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	4.0
DANN	Benign	0.62
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.75
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.11		Gain of glycosylation at P21 (P = 0.0551)
MVP		0.48
MPC		0.85
ClinPred		0.048	T
GERP RS		-1.5
PromoterAI		0.059	Neutral
Varity_R		0.028
gMVP		0.31
Mutation Taster		=98/2	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: rs751855283; hg19: chr1-113051949;