rs35415678

Positions:

Variant summary

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

The NM_004655.4(AXIN2):c.2062C>T(p.Leu688Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,678 control chromosomes in the GnomAD database, including 6,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1473 hom., cov: 33)

Exomes 𝑓: 0.060 ( 4681 hom. )

Consequence

AXIN2
NM_004655.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.31

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:

AXIN2 (HGNC:):

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=-0.55).

BP6

Variant 17-65536399-G-A is Benign according to our data. Variant chr17-65536399-G-A is described in ClinVar as [Benign]. Clinvar id is 259514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65536399-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 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.2062C>T	p.Leu688Leu	synonymous_variant	8/11	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.2062C>T	p.Leu688Leu	synonymous_variant	8/11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1867C>T	p.Leu623Leu	synonymous_variant	6/9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1867C>T	p.Leu623Leu	synonymous_variant	7/10	5		ENSP00000478916.1	E7ES00
AXIN2	ENST00000578251.1 linkuse as main transcript	n.284C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16801

AN:

152144

Hom.:

1455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.0595

Gnomad FIN

AF:

0.0724

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0444

Gnomad OTH

AF:

0.0927

GnomAD3 exomes

AF:

0.0911

AC:

22294

AN:

244814

Hom.:

1722

AF XY:

0.0834

AC XY:

11087

AN XY:

132880

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.271

Gnomad SAS exome

AF:

0.0583

Gnomad FIN exome

AF:

0.0705

Gnomad NFE exome

AF:

0.0420

Gnomad OTH exome

AF:

0.0717

GnomAD4 exome

AF:

0.0595

AC:

86973

AN:

1461416

Hom.:

4681

Cov.:

AF XY:

0.0584

AC XY:

42421

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.157

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.297

Gnomad4 SAS exome

AF:

0.0550

Gnomad4 FIN exome

AF:

0.0660

Gnomad4 NFE exome

AF:

0.0429

Gnomad4 OTH exome

AF:

0.0649

GnomAD4 genome

AF:

0.111

AC:

16862

AN:

152262

Hom.:

1473

Cov.:

AF XY:

0.114

AC XY:

8505

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.211

Gnomad4 AMR

AF:

0.150

Gnomad4 ASJ

AF:

0.0256

Gnomad4 EAS

AF:

0.268

Gnomad4 SAS

AF:

0.0585

Gnomad4 FIN

AF:

0.0724

Gnomad4 NFE

AF:

0.0444

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0667

Hom.:

268

Bravo

AF:

0.120

Asia WGS

AF:

0.193

AC:

670

AN:

3478

EpiCase

AF:

0.0402

EpiControl

AF:

0.0440

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	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	Myriad Genetics, Inc.	Jul 09, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16432638, 18790474) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The c.2062C>T in AXIN2 gene is a synonymous change that involves a conserved nucleotide. 5/5 splice-site tools in Alamut predict this variant not to have an impact on normal splicing. The variant is present in the control population dataset of ExAC at an allele frequency of 9%. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.014%, suggesting that it is a benign polymorphism. Classification information about the variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the 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

Aug 19, 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

-0.55

CADD

Benign

6.4

DANN

Benign

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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