17-65558473-G-C

Position:

• chr17-65558473-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004655.4(AXIN2):​c.148C>G​(p.Pro50Ala) 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 benign outcome for this variant. 14/19 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. P50S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11572155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.148C>G	p.Pro50Ala	missense_variant	2/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.148C>G	p.Pro50Ala	missense_variant	2/11	1	NM_004655.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.59
DEOGEN2	Benign	0.23	.;.;T;T;T;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.84	.;T;T;.;T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;.;.;N;.;.;.;N
REVEL	Benign	0.066
Sift	Benign	0.21	T;.;.;T;.;.;.;D
Sift4G	Benign	0.49	T;T;T;T;.;.;.;.
Polyphen		0.034	.;.;B;B;.;.;.;.
Vest4		0.23
MutPred		0.19		Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);Gain of MoRF binding (P = 0.0395);
MVP		0.42
MPC		0.25
ClinPred		0.10	T
GERP RS		2.8
gMVP		0.16

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: rs2240308; hg19: chr17-63554591;