chr17-65537545-G-C

Position:

• chr17-65537545-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004655.4(AXIN2):​c.1491C>G​(p.Cys497Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C497Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

Genes affected

AXIN2 (HGNC:904): (axin 2) The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1491C>G	p.Cys497Trp	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1491C>G	p.Cys497Trp	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1491C>G	p.Cys497Trp	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1491C>G	p.Cys497Trp	missense_variant	6/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.31	.;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.68	.;T;.
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.99	.;D;D
Vest4		0.73
MutPred		0.34		Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);
MVP		0.53
MPC		0.56
ClinPred		0.50	D
GERP RS		3.0
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-63533663;