17-65537801-T-C

Position:

chr17-65537801-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004655.4(AXIN2):c.1235A>G(p.Asn412Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,586,748 control chromosomes in the GnomAD database, including 165 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 157 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.0230

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=0.0022900105).

BP6

Variant 17-65537801-T-C is Benign according to our data. Variant chr17-65537801-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65537801-T-C is described in Lovd as [Benign]. Variant chr17-65537801-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00665 (1011/152122) while in subpopulation SAS AF= 0.0373 (180/4830). AF 95% confidence interval is 0.0328. There are 8 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.1235A>G	p.Asn412Ser	missense_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.1235A>G	p.Asn412Ser	missense_variant	6/11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1235A>G	p.Asn412Ser	missense_variant	5/9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1235A>G	p.Asn412Ser	missense_variant	6/10	5		ENSP00000478916.1	E7ES00

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1012

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0372

Gnomad FIN

AF:

0.00744

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00640

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00975

AC:

1997

AN:

204818

Hom.:

AF XY:

0.0117

AC XY:

1300

AN XY:

111560

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.0000625

Gnomad SAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.00709

Gnomad NFE exome

AF:

0.00620

Gnomad OTH exome

AF:

0.00876

GnomAD4 exome

AF:

0.00807

AC:

11577

AN:

1434626

Hom.:

157

Cov.:

AF XY:

0.00911

AC XY:

6474

AN XY:

711028

show subpopulations

Gnomad4 AFR exome

AF:

0.00492

Gnomad4 AMR exome

AF:

0.00419

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.0000514

Gnomad4 SAS exome

AF:

0.0413

Gnomad4 FIN exome

AF:

0.00751

Gnomad4 NFE exome

AF:

0.00601

Gnomad4 OTH exome

AF:

0.00879

GnomAD4 genome

AF:

0.00665

AC:

1011

AN:

152122

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

556

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00450

Gnomad4 AMR

AF:

0.00457

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0373

Gnomad4 FIN

AF:

0.00744

Gnomad4 NFE

AF:

0.00640

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00494

Hom.:

Bravo

AF:

0.00561

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00594

AC:

ESP6500EA

AF:

0.00479

AC:

ExAC

AF:

0.00959

AC:

1160

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	Variant summary: The c.1235A>G variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a neutral outcome. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 2.5% which includes 20 homozygous occurrences, strong evidence that this is a benign polymorphism. Muliple reputable clinical labs have classified this variant as benign. Due to the high allele frequency of the variant in the general population, this variant has been classified as Benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oligodontia-cancer predisposition syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Jan 13, 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. -

Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 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. -

AXIN2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.43

DANN

Benign

0.40

DEOGEN2

Benign

0.21

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.59

.;T;.

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.92

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.71

T;.;T

Sift4G

Benign

0.98

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.036

MVP

0.32

MPC

0.14

ClinPred

0.00014

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.059

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