rs1133683

Variant names:

• chr17-65537650-G-A
• rs1133683
• NM_004655.4:c.1386C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65537650-G-A
• chr17-65537650-G-C
• chr17-65537650-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004655.4(AXIN2):​c.1386C>T​(p.Pro462Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,570,832 control chromosomes in the GnomAD database, including 317,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (23264 hom., cov: 32)
  • Exomes 𝑓: 0.64 (293874 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.688
• Publications: 42 publications found

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]

AXIN2 Gene-Disease associations (from GenCC):

• oligodontia-cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-65537650-G-A is Benign according to our data. Variant chr17-65537650-G-A is described in ClinVar as Benign. ClinVar VariationId is 259510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.688 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1386C>T	p.Pro462Pro	synonymous_variant	Exon 6 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1386C>T	p.Pro462Pro	synonymous_variant	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1386C>T	p.Pro462Pro	synonymous_variant	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1386C>T	p.Pro462Pro	synonymous_variant	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80129 AN: 151668 Hom.: 23271 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.547

GnomAD2 exomes AF: 0.600 AC: 111518 AN: 185902 AF XY: 0.607

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.352

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.637 AC: 904596 AN: 1419046 Hom.: 293874 Cov.: 85 AF XY: 0.637 AC XY: 447561 AN XY: 702442

African (AFR) AF: 0.272 AC: 8959 AN: 32954

American (AMR) AF: 0.598 AC: 22319 AN: 37326

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 18290 AN: 25498

East Asian (EAS) AF: 0.340 AC: 12963 AN: 38124

South Asian (SAS) AF: 0.615 AC: 50996 AN: 82884

European-Finnish (FIN) AF: 0.619 AC: 27841 AN: 44960

Middle Eastern (MID) AF: 0.585 AC: 3288 AN: 5618

European-Non Finnish (NFE) AF: 0.663 AC: 724107 AN: 1092622

Other (OTH) AF: 0.607 AC: 35833 AN: 59060

GnomAD4 genome AF: 0.528 AC: 80138 AN: 151786 Hom.: 23264 Cov.: 32 AF XY: 0.526 AC XY: 38972 AN XY: 74106

African (AFR) AF: 0.279 AC: 11576 AN: 41458

American (AMR) AF: 0.561 AC: 8569 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2500 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1762 AN: 5020

South Asian (SAS) AF: 0.607 AC: 2917 AN: 4808

European-Finnish (FIN) AF: 0.618 AC: 6512 AN: 10544

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44291 AN: 67900

Other (OTH) AF: 0.540 AC: 1139 AN: 2108

Alfa AF: 0.600 Hom.: 5229

Bravo AF: 0.515

Asia WGS AF: 0.442 AC: 1539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oligodontia-cancer predisposition syndrome Benign:5

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The AXIN2 c.1386C>T variant affects a non-conserved nucleotide, resulting in no amino acid change. Mutation Taster predicts the variant is a polymorphism, and 5/5 Alamut algorithms predict no significant change to splicing. This variant was found in 35556/57014 control chromosomes (11148 homozygotes) at a frequency of 0.6236363, which is about 4390 times of the maximal expected frequency of a pathogenic ACIN2 allele (0.0001421), suggesting this variant is benign. The variant has been reported to possibly be associated with astrocytoma, however the odds ratio was not believable and the sample size was relatively small (Gunes_Mol Med Reports_2010). Taken together, this variant was classified as benign. -

Hereditary cancer-predisposing syndrome Benign:2

Sep 12, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Carcinoma of colon;C1837750:Oligodontia-cancer predisposition syndrome Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.7
DANN	Benign	0.89
PhyloP100		-0.69
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1133683; hg19: chr17-63533768; COSMIC: COSV61055294; COSMIC: COSV61055294;