chr17-65558189-A-G

Position:

chr17-65558189-A-G

Variant summary

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

The ENST00000307078.10(AXIN2):c.432T>C(p.Ile144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,613,946 control chromosomes in the GnomAD database, including 1,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 317 hom., cov: 32)

Exomes 𝑓: 0.018 ( 1183 hom. )

Consequence

AXIN2
ENST00000307078.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.117

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=-0.69).

BP6

Variant 17-65558189-A-G is Benign according to our data. Variant chr17-65558189-A-G is described in ClinVar as [Benign]. Clinvar id is 259515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65558189-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.117 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 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.432T>C	p.Ile144=	synonymous_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.432T>C	p.Ile144=	synonymous_variant	2/11	1	NM_004655.4	ENSP00000302625	P1

Frequencies

GnomAD3 genomes

AF:

0.0434

AC:

6600

AN:

151936

Hom.:

307

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0732

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0481

Gnomad FIN

AF:

0.0372

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00562

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0445

AC:

11190

AN:

251492

Hom.:

633

AF XY:

0.0398

AC XY:

5413

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0722

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.00744

Gnomad EAS exome

AF:

0.167

Gnomad SAS exome

AF:

0.0411

Gnomad FIN exome

AF:

0.0328

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.0272

GnomAD4 exome

AF:

0.0177

AC:

25866

AN:

1461892

Hom.:

1183

Cov.:

AF XY:

0.0174

AC XY:

12688

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0759

Gnomad4 AMR exome

AF:

0.118

Gnomad4 ASJ exome

AF:

0.00738

Gnomad4 EAS exome

AF:

0.166

Gnomad4 SAS exome

AF:

0.0398

Gnomad4 FIN exome

AF:

0.0295

Gnomad4 NFE exome

AF:

0.00436

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0436

AC:

6637

AN:

152054

Hom.:

317

Cov.:

AF XY:

0.0490

AC XY:

3641

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0734

Gnomad4 AMR

AF:

0.111

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.0482

Gnomad4 FIN

AF:

0.0372

Gnomad4 NFE

AF:

0.00562

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0144

Hom.:

111

Bravo

AF:

0.0492

Asia WGS

AF:

0.0970

AC:

337

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Oligodontia-cancer predisposition syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Myriad Genetics, Inc.	Jun 26, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The AXIN2 c.432T>C 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 4851/121408 control chromosomes (257 homozygotes) at a frequency of 0.0399562, which is about 281 times of the maximal expected frequency of a pathogenic AXIN2 allele (0.0001421), suggesting this variant is benign. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.8

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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