2-218871610-C-A

Variant names:

• chr2-218871610-C-A
• rs1463926853
• NM_006522.4:c.427C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006522.4(WNT6):​c.427C>A​(p.Pro143Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,334,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 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. P143A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: WNT6 NM_006522.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.34
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.427C>A	p.Pro143Thr	missense	Exon 3 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.427C>A	p.Pro143Thr	missense	Exon 3 of 4	ENSP00000233948.3	Q9Y6F9
	WNT6	ENST00000486233.1	TSL:5	n.279C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1334838 Hom.: 0 Cov.: 32 AF XY: 0.00000456 AC XY: 3 AN XY: 657560

African (AFR) AF: 0.00 AC: 0 AN: 27378

American (AMR) AF: 0.00 AC: 0 AN: 26750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21648

East Asian (EAS) AF: 0.00 AC: 0 AN: 30812

South Asian (SAS) AF: 0.00 AC: 0 AN: 70206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41690

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4098

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1057208

Other (OTH) AF: 0.00 AC: 0 AN: 55048

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.22
Sift	Benign	0.34	T
Sift4G	Benign	0.43	T
Polyphen		0.95	P
Vest4		0.32
MutPred		0.37		Gain of phosphorylation at P143 (P = 0.0035)
MVP		0.69
MPC		0.71
ClinPred		0.28	T
GERP RS		3.6
Varity_R		0.067
gMVP		0.50
Mutation Taster		=74/26	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: rs1463926853; hg19: chr2-219736332;