chr17-65537671-T-C

Position:

chr17-65537671-T-C

Variant summary

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

The NM_004655.4(AXIN2):c.1365A>G(p.Pro455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 1,559,288 control chromosomes in the GnomAD database, including 625,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P455P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.90 ( 62168 hom., cov: 32)

Exomes 𝑓: 0.89 ( 563316 hom. )

Consequence

AXIN2
NM_004655.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -7.66

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-65537671-T-C is Benign according to our data. Variant chr17-65537671-T-C is described in ClinVar as [Benign]. Clinvar id is 259509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65537671-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-7.66 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.1365A>G	p.Pro455=	synonymous_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
AXIN2	ENST00000307078.10 linkuse as main transcript	c.1365A>G	p.Pro455=	synonymous_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1365A>G	p.Pro455=	synonymous_variant	5/9	1
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1365A>G	p.Pro455=	synonymous_variant	6/10	5

Frequencies

GnomAD3 genomes

AF:

0.904

AC:

137242

AN:

151752

Hom.:

62111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.932

Gnomad AMI

AF:

0.896

Gnomad AMR

AF:

0.897

Gnomad ASJ

AF:

0.948

Gnomad EAS

AF:

0.816

Gnomad SAS

AF:

0.951

Gnomad FIN

AF:

0.899

Gnomad MID

AF:

0.965

Gnomad NFE

AF:

0.891

Gnomad OTH

AF:

0.916

GnomAD3 exomes

AF:

0.902

AC:

154632

AN:

171458

Hom.:

69841

AF XY:

0.904

AC XY:

82746

AN XY:

91536

show subpopulations

Gnomad AFR exome

AF:

0.933

Gnomad AMR exome

AF:

0.891

Gnomad ASJ exome

AF:

0.948

Gnomad EAS exome

AF:

0.824

Gnomad SAS exome

AF:

0.955

Gnomad FIN exome

AF:

0.894

Gnomad NFE exome

AF:

0.892

Gnomad OTH exome

AF:

0.910

GnomAD4 exome

AF:

0.894

AC:

1258681

AN:

1407418

Hom.:

563316

Cov.:

AF XY:

0.896

AC XY:

623035

AN XY:

695252

show subpopulations

Gnomad4 AFR exome

AF:

0.937

Gnomad4 AMR exome

AF:

0.893

Gnomad4 ASJ exome

AF:

0.951

Gnomad4 EAS exome

AF:

0.839

Gnomad4 SAS exome

AF:

0.956

Gnomad4 FIN exome

AF:

0.893

Gnomad4 NFE exome

AF:

0.889

Gnomad4 OTH exome

AF:

0.898

GnomAD4 genome

AF:

0.904

AC:

137359

AN:

151870

Hom.:

62168

Cov.:

AF XY:

0.905

AC XY:

67149

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.932

Gnomad4 AMR

AF:

0.897

Gnomad4 ASJ

AF:

0.948

Gnomad4 EAS

AF:

0.816

Gnomad4 SAS

AF:

0.952

Gnomad4 FIN

AF:

0.899

Gnomad4 NFE

AF:

0.891

Gnomad4 OTH

AF:

0.917

Alfa

AF:

0.899

Hom.:

16007

Bravo

AF:

0.904

Asia WGS

AF:

0.874

AC:

3043

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	Aug 17, 2016	Variant summary: The AXIN2 c.1365A>G (p.Pro455Pro) variant causes a synonymous change involving a non-conserved nucleotide. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.914 (39107/42768 chromosomes, 17839 homozygotes), therefore suggesting that the G allele is the major allele (most commonly observed) found in the general population. Therefore, the variant of interest has been 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

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.48

DANN

Benign

0.65

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