rs74006838

Variant summary

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

The NM_004655.4(AXIN2):c.1952C>T(p.Ser651Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S651W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.889

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=0.0041804314).

BP6

Variant 17-65536509-G-A is Benign according to our data. Variant chr17-65536509-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00118 (180/152352) while in subpopulation AFR AF= 0.00418 (174/41586). AF 95% confidence interval is 0.00368. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.1952C>T	p.Ser651Leu	missense_variant	8/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
AXIN2	ENST00000307078.10 linkuse as main transcript	c.1952C>T	p.Ser651Leu	missense_variant	8/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1757C>T	p.Ser586Leu	missense_variant	6/9	1
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1757C>T	p.Ser586Leu	missense_variant	7/10	5
AXIN2	ENST00000578251.1 linkuse as main transcript	n.174C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000269

AC:

AN:

245260

Hom.:

AF XY:

0.000233

AC XY:

AN XY:

133194

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000738

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461490

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00343

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152352

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00418

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0256

Hom.:

2354

Bravo

AF:

0.00144

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000395

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2021	This variant is associated with the following publications: (PMID: 28481359) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2017	Variant summary: The AXIN2 c.1952C>T (p.Ser651Leu) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 47/117962 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004176 (40/9578). This frequency is about 29 times the estimated maximal expected allele frequency of a pathogenic AXIN2 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. An internal LCA sample reports the variant to co-occur with two MUTYH pathogenic variants, c.536A>G and c.1187G>A. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 03, 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. -

Oligodontia-cancer predisposition syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2022

- -

Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 27, 2022

- -

AXIN2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

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

0.072

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

Cadd

Benign

0.082

Dann

Benign

0.88

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.0

N;.;N

REVEL

Benign

0.079

Sift

Benign

0.37

T;.;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0080

.;B;B

Vest4

0.25

MVP

0.11

MPC

0.16

ClinPred

0.0031

GERP RS

-10

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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