17-65530080-C-T

Position:

chr17-65530080-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004655.4(AXIN2):c.2428G>A(p.Asp810Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,614,174 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 5.01

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012767017).

BP6

Variant 17-65530080-C-T is Benign according to our data. Variant chr17-65530080-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127945.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152306) while in subpopulation AFR AF= 0.00392 (163/41568). AF 95% confidence interval is 0.00343. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.2428G>A	p.Asp810Asn	missense_variant	11/11	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.2428G>A	p.Asp810Asn	missense_variant	11/11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.2233G>A	p.Asp745Asn	missense_variant	9/9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 linkuse as main transcript	c.2233G>A	p.Asp745Asn	missense_variant	10/10	5		ENSP00000478916.1	E7ES00

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251282

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000161

AC:

236

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00541

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152306

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.00134

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000346

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 2019	This alteration is classified as likely 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

This variant is denoted AXIN2 c.2428G>A at the cDNA level, p.Asp810Asn (D810N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant was observed in at least one individual with breast or gynecological cancer, as well as individuals with colon cancer (DeRycke 2017, Dominguez-Valentin 2018). AXIN2 Asp810Asn was observed at an allele frequency of 0.35% (83/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the DIX domain (Salahshor 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether AXIN2 Asp810Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Oligodontia-cancer predisposition syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

AXIN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2021

This variant is classified as likely 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

0.070

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

.;T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.84

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Benign

0.13

Sift

Benign

0.13

T;.;D

Sift4G

Benign

0.086

T;T;T

Polyphen

0.14

.;B;B

Vest4

0.25

MVP

0.39

MPC

0.21

ClinPred

0.063

GERP RS

3.6

gMVP

0.35

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