chr17-65558473-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004655.4(AXIN2):​c.148C>T​(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,605,836 control chromosomes in the GnomAD database, including 201,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 14296 hom., cov: 32)
Exomes 𝑓: 0.50 ( 187519 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

1
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.14
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.7431378E-4).
BP6
Variant 17-65558473-G-A is Benign according to our data. Variant chr17-65558473-G-A is described in ClinVar as [Benign]. Clinvar id is 259511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65558473-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.148C>T p.Pro50Ser missense_variant Exon 2 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.148C>T p.Pro50Ser missense_variant Exon 2 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
ENSG00000266076ENST00000577662.1 linkn.*324C>T non_coding_transcript_exon_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3
ENSG00000266076ENST00000577662.1 linkn.*324C>T 3_prime_UTR_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3

Frequencies

GnomAD3 genomes
AF:
0.396
AC:
60184
AN:
151988
Hom.:
14295
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.128
Gnomad AMI
AF:
0.549
Gnomad AMR
AF:
0.474
Gnomad ASJ
AF:
0.470
Gnomad EAS
AF:
0.326
Gnomad SAS
AF:
0.463
Gnomad FIN
AF:
0.495
Gnomad MID
AF:
0.373
Gnomad NFE
AF:
0.521
Gnomad OTH
AF:
0.391
GnomAD2 exomes
AF:
0.474
AC:
117123
AN:
247006
AF XY:
0.479
show subpopulations
Gnomad AFR exome
AF:
0.114
Gnomad AMR exome
AF:
0.547
Gnomad ASJ exome
AF:
0.474
Gnomad EAS exome
AF:
0.325
Gnomad FIN exome
AF:
0.499
Gnomad NFE exome
AF:
0.525
Gnomad OTH exome
AF:
0.477
GnomAD4 exome
AF:
0.502
AC:
729689
AN:
1453730
Hom.:
187519
Cov.:
79
AF XY:
0.500
AC XY:
361223
AN XY:
721970
show subpopulations
Gnomad4 AFR exome
AF:
0.111
AC:
3709
AN:
33340
Gnomad4 AMR exome
AF:
0.537
AC:
23772
AN:
44304
Gnomad4 ASJ exome
AF:
0.475
AC:
12130
AN:
25552
Gnomad4 EAS exome
AF:
0.316
AC:
12507
AN:
39550
Gnomad4 SAS exome
AF:
0.468
AC:
39964
AN:
85478
Gnomad4 FIN exome
AF:
0.514
AC:
27306
AN:
53138
Gnomad4 NFE exome
AF:
0.524
AC:
579872
AN:
1106654
Gnomad4 Remaining exome
AF:
0.472
AC:
28333
AN:
59992
Heterozygous variant carriers
0
23700
47401
71101
94802
118502
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
16514
33028
49542
66056
82570
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.396
AC:
60181
AN:
152106
Hom.:
14296
Cov.:
32
AF XY:
0.396
AC XY:
29414
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.127
AC:
0.127468
AN:
0.127468
Gnomad4 AMR
AF:
0.474
AC:
0.474156
AN:
0.474156
Gnomad4 ASJ
AF:
0.470
AC:
0.470317
AN:
0.470317
Gnomad4 EAS
AF:
0.326
AC:
0.326467
AN:
0.326467
Gnomad4 SAS
AF:
0.465
AC:
0.465116
AN:
0.465116
Gnomad4 FIN
AF:
0.495
AC:
0.495279
AN:
0.495279
Gnomad4 NFE
AF:
0.521
AC:
0.521206
AN:
0.521206
Gnomad4 OTH
AF:
0.386
AC:
0.386256
AN:
0.386256
Heterozygous variant carriers
0
1679
3358
5038
6717
8396
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
582
1164
1746
2328
2910
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.492
Hom.:
69630
Bravo
AF:
0.385
TwinsUK
AF:
0.520
AC:
1929
ALSPAC
AF:
0.529
AC:
2040
ESP6500AA
AF:
0.135
AC:
596
ESP6500EA
AF:
0.528
AC:
4539
ExAC
AF:
0.469
AC:
56987
Asia WGS
AF:
0.366
AC:
1274
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oligodontia-cancer predisposition syndrome Benign:5
Jun 25, 2024
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Jul 14, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:4
Nov 23, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Apr 26, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: The c.148C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant is found in 56448/119156 control chromosomes (14394 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4737319, which is about 3335 times greater than the maximal expected frequency of a pathogenic allele (0.0001421), suggesting this variant is a very common benign polymorphism. In a case-control study, authors found that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed (Kanzaki_IJMM_2006). Taken together, this variant was classified as Benign. -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26514524, 29114927, 28204848, 27153395, 16820935, 19065536) -

Hereditary cancer-predisposing syndrome Benign:1
Sep 10, 2018
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
21
DANN
Benign
0.68
DEOGEN2
Benign
0.22
.;.;T;T;T;.;.;.
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.52
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.68
.;T;T;.;T;T;T;T
MetaRNN
Benign
0.00017
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.0
N;.;.;N;.;.;.;N
REVEL
Benign
0.13
Sift
Benign
0.37
T;.;.;T;.;.;.;T
Sift4G
Benign
0.57
T;T;T;T;.;.;.;.
Polyphen
0.0
.;.;B;B;.;.;.;.
Vest4
0.033
MPC
0.18
ClinPred
0.0076
T
GERP RS
2.8
gMVP
0.17
Mutation Taster
=93/7
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs2240308; hg19: chr17-63554591; COSMIC: COSV61057354; API