1-112509285-A-G

Variant names:

• chr1-112509285-A-G
• rs1003281577
• NM_024494.3:c.23A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024494.3(WNT2B):​c.23A>G​(p.Glu8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,540,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: WNT2B NM_024494.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25034454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT2B	NM_024494.3	c.23A>G	p.Glu8Gly	missense_variant	Exon 1 of 5	ENST00000369684.5	NP_078613.1
WNT2B	NM_004185.4	c.126-5589A>G		intron_variant	Intron 2 of 5		NP_004176.2
WNT2B	NM_001291880.1	c.-94-5589A>G		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.23A>G	p.Glu8Gly	missense_variant	Exon 1 of 5	1	NM_024494.3	ENSP00000358698.4
WNT2B	ENST00000369686.9	c.126-5589A>G		intron_variant	Intron 2 of 5	1		ENSP00000358700.4
WNT2B	ENST00000256640.9	c.-94-5589A>G		intron_variant	Intron 1 of 4	2		ENSP00000256640.5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151932 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000354 AC: 5 AN: 141104 AF XY: 0.0000255

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000258

GnomAD4 exome AF: 0.0000216 AC: 30 AN: 1388848 Hom.: 0 Cov.: 32 AF XY: 0.0000247 AC XY: 17 AN XY: 686896

African (AFR) AF: 0.00 AC: 0 AN: 30228

American (AMR) AF: 0.0000856 AC: 3 AN: 35044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24536

East Asian (EAS) AF: 0.00 AC: 0 AN: 35456

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40890

Middle Eastern (MID) AF: 0.000743 AC: 3 AN: 4040

European-Non Finnish (NFE) AF: 0.0000194 AC: 21 AN: 1081034

Other (OTH) AF: 0.0000347 AC: 2 AN: 57672

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151932 Hom.: 0 Cov.: 33 AF XY: 0.0000809 AC XY: 6 AN XY: 74198

African (AFR) AF: 0.0000725 AC: 3 AN: 41376

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.24
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.022	B
Vest4		0.36
MVP		0.83
MPC		1.1
ClinPred		0.13	T
GERP RS		3.9
PromoterAI		0.0019	Neutral
Varity_R		0.11
gMVP		0.63
Mutation Taster		=90/10	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: rs1003281577; hg19: chr1-113051907;