chr17-65558473-G-A

Position:

chr17-65558473-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004655.4(AXIN2):c.148C>T(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,605,836 control chromosomes in the GnomAD database, including 201,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 14296 hom., cov: 32)

Exomes 𝑓: 0.50 ( 187519 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.14

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7431378E-4).

BP6

Variant 17-65558473-G-A is Benign according to our data. Variant chr17-65558473-G-A is described in ClinVar as [Benign]. Clinvar id is 259511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65558473-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 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.148C>T	p.Pro50Ser	missense_variant	2/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10 linkuse as main transcript	c.148C>T	p.Pro50Ser	missense_variant	2/11	1	NM_004655.4	ENSP00000302625	P1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60184

AN:

151988

Hom.:

14295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.470

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.463

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.521

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.474

AC:

117123

AN:

247006

Hom.:

29707

AF XY:

0.479

AC XY:

63861

AN XY:

133402

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.547

Gnomad ASJ exome

AF:

0.474

Gnomad EAS exome

AF:

0.325

Gnomad SAS exome

AF:

0.469

Gnomad FIN exome

AF:

0.499

Gnomad NFE exome

AF:

0.525

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.502

AC:

729689

AN:

1453730

Hom.:

187519

Cov.:

AF XY:

0.500

AC XY:

361223

AN XY:

721970

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.537

Gnomad4 ASJ exome

AF:

0.475

Gnomad4 EAS exome

AF:

0.316

Gnomad4 SAS exome

AF:

0.468

Gnomad4 FIN exome

AF:

0.514

Gnomad4 NFE exome

AF:

0.524

Gnomad4 OTH exome

AF:

0.472

GnomAD4 genome

AF:

0.396

AC:

60181

AN:

152106

Hom.:

14296

Cov.:

AF XY:

0.396

AC XY:

29414

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.474

Gnomad4 ASJ

AF:

0.470

Gnomad4 EAS

AF:

0.326

Gnomad4 SAS

AF:

0.465

Gnomad4 FIN

AF:

0.495

Gnomad4 NFE

AF:

0.521

Gnomad4 OTH

AF:

0.386

Alfa

AF:

0.491

Hom.:

33055

Bravo

AF:

0.385

TwinsUK

AF:

0.520

AC:

1929

ALSPAC

AF:

0.529

AC:

2040

ESP6500AA

AF:

0.135

AC:

596

ESP6500EA

AF:

0.528

AC:

4539

ExAC

AF:

0.469

AC:

56987

Asia WGS

AF:

0.366

AC:

1274

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

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	Illumina Laboratory Services, Illumina	Mar 06, 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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 25, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26514524, 29114927, 28204848, 27153395, 16820935, 19065536) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.148C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant is found in 56448/119156 control chromosomes (14394 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4737319, which is about 3335 times greater than the maximal expected frequency of a pathogenic allele (0.0001421), suggesting this variant is a very common benign polymorphism. In a case-control study, authors found that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed (Kanzaki_IJMM_2006). Taken together, this variant was classified as Benign. -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.22

.;.;T;T;T;.;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.68

.;T;T;.;T;T;T;T

MetaRNN

Benign

0.00017

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

0.00081

P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

N;.;.;N;.;.;.;N

REVEL

Benign

0.13

Sift

Benign

0.37

T;.;.;T;.;.;.;T

Sift4G

Benign

0.57

T;T;T;T;.;.;.;.

Polyphen

0.0

.;.;B;B;.;.;.;.

Vest4

0.033

MPC

0.18

ClinPred

0.0076

GERP RS

2.8

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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