rs1060502134

Variant names:

• chr17-65541510-C-G
• rs1060502134
• NM_004655.4:c.1004G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-65541510-C-G
• chr17-65541510-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004655.4(AXIN2):​c.1004G>C​(p.Arg335Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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]

ENSG00000266076 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1004G>C	p.Arg335Thr	missense_variant	Exon 4 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1004G>C	p.Arg335Thr	missense_variant	Exon 4 of 11	1	NM_004655.4	ENSP00000302625.5
ENSG00000266076	ENST00000577662.1	n.*1180G>C		non_coding_transcript_exon_variant	Exon 6 of 7	2		ENSP00000462418.1
ENSG00000266076	ENST00000577662.1	n.*1180G>C		3_prime_UTR_variant	Exon 6 of 7	2		ENSP00000462418.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R335T variant (also known as c.1004G>C), located in coding exon 3 of the AXIN2 gene, results from a G to C substitution at nucleotide position 1004. The arginine at codon 335 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.60	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D;.;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.84
MutPred		0.35		Gain of ubiquitination at K330 (P = 0.0329);Gain of ubiquitination at K330 (P = 0.0329);Gain of ubiquitination at K330 (P = 0.0329);
MVP		0.81
MPC		0.87
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.55

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: rs1060502134; hg19: chr17-63537628;