17-65537814-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004655.4(AXIN2):​c.1222G>A​(p.Glu408Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000153 in 1,572,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

1
3
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.62
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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10790479).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AXIN2NM_004655.4 linkuse as main transcriptc.1222G>A p.Glu408Lys missense_variant 6/11 ENST00000307078.10 NP_004646.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkuse as main transcriptc.1222G>A p.Glu408Lys missense_variant 6/111 NM_004655.4 ENSP00000302625 P1
AXIN2ENST00000375702.5 linkuse as main transcriptc.1222G>A p.Glu408Lys missense_variant 5/91 ENSP00000364854
AXIN2ENST00000618960.4 linkuse as main transcriptc.1222G>A p.Glu408Lys missense_variant 6/105 ENSP00000478916

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152024
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000671
AC:
13
AN:
193720
Hom.:
0
AF XY:
0.0000474
AC XY:
5
AN XY:
105408
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000397
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000233
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000127
AC:
18
AN:
1420528
Hom.:
0
Cov.:
36
AF XY:
0.0000142
AC XY:
10
AN XY:
702456
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000287
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000641
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152024
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74238
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000421
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000579
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsAug 27, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the AXIN2 protein (p.Glu408Lys). This variant is present in population databases (rs749846538, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medulloblastoma (PMID: 17373666). ClinVar contains an entry for this variant (Variation ID: 408784). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2022The p.E408K variant (also known as c.1222G>A), located in coding exon 5 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 25, 2022- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 23, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with medulloblastoma and absent in unaffected controls (PMID: 17373666); This variant is associated with the following publications: (PMID: 15735151, 17373666) -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 09, 2023- -
Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 22, 2022- -
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 02, 2024- -
AXIN2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 14, 2024The AXIN2 c.1222G>A variant is predicted to result in the amino acid substitution p.Glu408Lys. This variant has been reported in an individual with medulloblastoma (Koch et al. 2007. PubMed ID: 17373666). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/408784/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;T;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.83
.;T;.
M_CAP
Pathogenic
0.64
D
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-0.45
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.8
N;.;N
REVEL
Benign
0.25
Sift
Benign
0.051
T;.;T
Sift4G
Benign
0.21
T;T;T
Polyphen
0.38
.;B;B
Vest4
0.31
MutPred
0.23
Gain of ubiquitination at E408 (P = 9e-04);Gain of ubiquitination at E408 (P = 9e-04);Gain of ubiquitination at E408 (P = 9e-04);
MVP
0.69
MPC
0.25
ClinPred
0.097
T
GERP RS
5.2
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
gMVP
0.22

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.

Other links and lift over

dbSNP: rs749846538; hg19: chr17-63533932; COSMIC: COSV61061853; COSMIC: COSV61061853; API