rs201460658

chr17-65537786-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004655.4(AXIN2):c.1250C>T(p.Ala417Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,586,630 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. A417E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00062 (5 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.305

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033774674).
• BP6: Variant 17-65537786-G-A is Benign according to our data. Variant chr17-65537786-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65537786-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000848 (129/152098) while in subpopulation EAS AF= 0.0201 (102/5066). AF 95% confidence interval is 0.017. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1250C>T	p.Ala417Val	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1250C>T	p.Ala417Val	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1250C>T	p.Ala417Val	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1250C>T	p.Ala417Val	missense_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 151980 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0203

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00198 AC: 399 AN: 201782 Hom.: 1 AF XY: 0.00180 AC XY: 198 AN XY: 109726

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0238

Gnomad SAS exome AF: 0.000426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000687

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.000620 AC: 889 AN: 1434532 Hom.: 5 Cov.: 37 AF XY: 0.000561 AC XY: 399 AN XY: 710880

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.0000491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0193

Gnomad4 SAS exome AF: 0.000377

Gnomad4 FIN exome AF: 0.0000585

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000848 AC: 129 AN: 152098 Hom.: 0 Cov.: 34 AF XY: 0.000969 AC XY: 72 AN XY: 74330

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.00102

ExAC AF: 0.00155 AC: 187

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oligodontia-cancer predisposition syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2018	This 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 submitter	clinical testing	Vantari Genetics	Jan 22, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 31, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	AXIN2: BP1, BP4, BS1:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 25, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.0
Dann	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.26	.;B;B
Vest4		0.088
MVP		0.56
MPC		0.18
ClinPred		0.0027	T
GERP RS		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs201460658; hg19: chr17-63533904; COSMIC: COSV61060069; COSMIC: COSV61060069;