chr17-65536321-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004655.4(AXIN2):​c.2140C>T​(p.Arg714Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000789 in 1,608,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense, splice_region

Scores

3
11
4
Splicing: ADA: 0.06604
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.729
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010754108).
BP6
Variant 17-65536321-G-A is Benign according to our data. Variant chr17-65536321-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240007.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000919 (14/152330) while in subpopulation EAS AF= 0.0027 (14/5188). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AXIN2NM_004655.4 linkc.2140C>T p.Arg714Trp missense_variant, splice_region_variant 8/11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.2140C>T p.Arg714Trp missense_variant, splice_region_variant 8/111 NM_004655.4 ENSP00000302625.5 Q9Y2T1
AXIN2ENST00000375702.5 linkc.1945C>T p.Arg649Trp missense_variant, splice_region_variant 6/91 ENSP00000364854.5 E7ES00
AXIN2ENST00000618960.4 linkc.1945C>T p.Arg649Trp missense_variant, splice_region_variant 7/105 ENSP00000478916.1 E7ES00
AXIN2ENST00000578251.1 linkn.362C>T splice_region_variant, non_coding_transcript_exon_variant 1/33

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00269
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000261
AC:
61
AN:
233328
Hom.:
0
AF XY:
0.000229
AC XY:
29
AN XY:
126890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00326
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000196
Gnomad OTH exome
AF:
0.000173
GnomAD4 exome
AF:
0.0000776
AC:
113
AN:
1456454
Hom.:
0
Cov.:
32
AF XY:
0.0000815
AC XY:
59
AN XY:
724120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00245
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00270
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000200
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.000280
AC:
34
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 13, 2019The AXIN2 c.2140C>T; p.Arg714Trp variant (rs148765149), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 240007). This variant is found in the general East Asian population with an allele frequency of 0.3% (63/19344 alleles) in the Genome Aggregation Database. The arginine at codon 714 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Given the high allele frequency in the East Asian population, this variant may be a benign polymorphism; however, due to insufficient information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 29, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with colorectal cancer demonstrating microsatellite instability (MSI-H), in an individual with serrated polyposis syndrome, and in an individual with multiple primary cancers (PMID: 31769227, 36419139, 36896836); This variant is associated with the following publications: (PMID: 22895193, Wei2020[CaseReport], 34426522, 15735151, 31769227, 36419139, 36896836) -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 23, 2021This alteration is classified as likely 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. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Nov 15, 2021- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Oligodontia-cancer predisposition syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
AXIN2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 07, 2020This variant is classified as likely 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
0.19
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
.;T;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.95
.;D;.
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.011
T;T;T
MetaSVM
Uncertain
-0.21
T
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.9
D;.;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0010
D;.;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.63
MVP
0.48
MPC
0.73
ClinPred
0.19
T
GERP RS
3.4
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.066
dbscSNV1_RF
Benign
0.23
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.

Other links and lift over

dbSNP: rs148765149; hg19: chr17-63532439; COSMIC: COSV61059041; COSMIC: COSV61059041; API