2-218871631-G-A

Variant names:

• chr2-218871631-G-A
• rs969854226
• NM_006522.4:c.448G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006522.4(WNT6):​c.448G>A​(p.Gly150Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,320,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WNT6 NM_006522.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.644

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT6	NM_006522.4	c.448G>A	p.Gly150Ser	missense_variant	Exon 3 of 4	ENST00000233948.4	NP_006513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT6	ENST00000233948.4	c.448G>A	p.Gly150Ser	missense_variant	Exon 3 of 4	1	NM_006522.4	ENSP00000233948.3
WNT6	ENST00000486233.1	n.300G>A		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1320094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 648320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.448G>A (p.G150S) alteration is located in exon 3 (coding exon 3) of the WNT6 gene. This alteration results from a G to A substitution at nucleotide position 448, causing the glycine (G) at amino acid position 150 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.40
Sift	Benign	0.41	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.41		Gain of glycosylation at G150 (P = 0);
MVP		0.82
MPC		0.75
ClinPred		0.37	T
GERP RS		4.0
Varity_R		0.096
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs969854226; hg19: chr2-219736353;