rs1133683

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.53 ( 23264 hom., cov: 32)

Exomes 𝑓: 0.64 ( 293874 hom. )

Consequence

AXIN2
NM_004655.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.688

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65537650-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.1386C>T	p.Pro462Pro	synonymous_variant	6/11	ENST00000307078.10	NP_004646.3	Q9Y2T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AXIN2	ENST00000307078.10 linkuse as main transcript	c.1386C>T	p.Pro462Pro	synonymous_variant	6/11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1386C>T	p.Pro462Pro	synonymous_variant	5/9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1386C>T	p.Pro462Pro	synonymous_variant	6/10	5		ENSP00000478916.1	E7ES00

Frequencies

GnomAD3 genomes

AF:

0.528

AC:

80129

AN:

151668

Hom.:

23271

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.600

AC:

111518

AN:

185902

Hom.:

34815

AF XY:

0.607

AC XY:

60563

AN XY:

99822

show subpopulations

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 SAS exome

AF:

0.615

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.:

AF XY:

0.637

AC XY:

447561

AN XY:

702442

show subpopulations

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.598

Gnomad4 ASJ exome

AF:

0.717

Gnomad4 EAS exome

AF:

0.340

Gnomad4 SAS exome

AF:

0.615

Gnomad4 FIN exome

AF:

0.619

Gnomad4 NFE exome

AF:

0.663

Gnomad4 OTH exome

AF:

0.607

GnomAD4 genome

AF:

0.528

AC:

80138

AN:

151786

Hom.:

23264

Cov.:

AF XY:

0.526

AC XY:

38972

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.279

Gnomad4 AMR

AF:

0.561

Gnomad4 ASJ

AF:

0.720

Gnomad4 EAS

AF:

0.351

Gnomad4 SAS

AF:

0.607

Gnomad4 FIN

AF:

0.618

Gnomad4 NFE

AF:

0.652

Gnomad4 OTH

AF:

0.540

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

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Oligodontia-cancer predisposition syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 03, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 12, 2023	- -

Carcinoma of colon;C1837750:Oligodontia-cancer predisposition syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.7

DANN

Benign

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over