NM_006522.4:c.839G>A

Variant names:

• chr2-218873586-G-A
• rs567728114
• NM_006522.4:c.839G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006522.4(WNT6):​c.839G>A​(p.Gly280Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,545,736 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 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: WNT6 NM_006522.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

Genes affected

WNT6 (HGNC:12785): (Wnt family member 6) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It is overexpressed in cervical cancer cell line and strongly coexpressed with another family member, WNT10A, in colorectal cancer cell line. The gene overexpression may play key roles in carcinogenesis. This gene and the WNT10A gene are clustered in the chromosome 2q35 region. The protein encoded by this gene is 97% identical to the mouse Wnt6 protein at the amino acid level. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0350945).
• BS2: High AC in GnomAd4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006522.4. 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
	WNT6	NM_006522.4	MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 4 of 4	NP_006513.1	Q9Y6F9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT6	ENST00000233948.4	TSL:1 MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 4 of 4	ENSP00000233948.3	Q9Y6F9

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000140 AC: 2 AN: 142674 AF XY: 0.0000127

Gnomad AFR exome AF: 0.000315

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 25 AN: 1393390 Hom.: 0 Cov.: 31 AF XY: 0.0000174 AC XY: 12 AN XY: 688454

African (AFR) AF: 0.000798 AC: 25 AN: 31310

American (AMR) AF: 0.00 AC: 0 AN: 38634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35698

South Asian (SAS) AF: 0.00 AC: 0 AN: 80004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082030

Other (OTH) AF: 0.00 AC: 0 AN: 57970

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 7 AN XY: 74510

African (AFR) AF: 0.000457 AC: 19 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.00000951 AC: 1

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	0.099
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.32	N
PhyloP100		2.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.12
Sift	Benign	0.68	T
Sift4G	Benign	0.85	T
Polyphen		0.0020	B
Vest4		0.040
MutPred		0.38		Loss of methylation at R281 (P = 0.0374)
MVP		0.12
MPC		1.8
ClinPred		0.019	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.77
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: rs567728114; hg19: chr2-219738308;