rs1555583751

Variant names:

• chr17-65558514-C-T
• rs1555583751
• NM_004655.4:c.107G>A

Variant summary

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

The NM_004655.4(AXIN2):​c.107G>A​(p.Cys36Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.86

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22744927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.107G>A	p.Cys36Tyr	missense_variant	Exon 2 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.107G>A	p.Cys36Tyr	missense_variant	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5
ENSG00000266076	ENST00000577662.1	n.*283G>A		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000462418.1
ENSG00000266076	ENST00000577662.1	n.*283G>A		3_prime_UTR_variant	Exon 4 of 7	2		ENSP00000462418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461328 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Mar 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with a AXIN2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 36 of the AXIN2 protein (p.Cys36Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. In summary, this variant has uncertain impact on AXIN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C36Y variant (also known as c.107G>A), located in coding exon 1 of the AXIN2 gene, results from a G to A substitution at nucleotide position 107. The cysteine at codon 36 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Benign	0.30	.;.;T;T;T;.;.;.
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.69	.;T;T;.;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;.;.;N;.;.;.;N
REVEL	Benign	0.18
Sift	Benign	0.45	T;.;.;T;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;.;.;.;.
Polyphen		1.0	.;.;D;D;.;.;.;.
Vest4		0.71
MutPred		0.19		Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);Gain of phosphorylation at C36 (P = 0.0035);
MVP		0.58
MPC		0.76
ClinPred		0.48	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.40

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: rs1555583751; hg19: chr17-63554632;