rs1299440644

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004655.4(AXIN2):c.2309delT(p.Phe770SerfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F770F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.89

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

oligodontia-cancer predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
craniosynostosis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

AXIN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-65534007-GA-G is Pathogenic according to our data. Variant chr17-65534007-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 533178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4 link	c.2309delT	p.Phe770SerfsTer12	frameshift_variant	Exon 10 of 11	ENST00000307078.10	NP_004646.3	Q9Y2T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AXIN2	ENST00000307078.10 link	c.2309delT	p.Phe770SerfsTer12	frameshift_variant	Exon 10 of 11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 link	c.2114delT	p.Phe705SerfsTer12	frameshift_variant	Exon 8 of 9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 link	c.2114delT	p.Phe705SerfsTer12	frameshift_variant	Exon 9 of 10	5		ENSP00000478916.1	E7ES00
AXIN2	ENST00000578251.1 link	n.531delT		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251496

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome

Pathogenic:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe770Serfs*12) in the AXIN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AXIN2 are known to be pathogenic (PMID: 15042511, 21416598). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 533178). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 20, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2309delT variant, located in coding exon 9 of the AXIN2 gene, results from a deletion of one nucleotide at nucleotide position 2309, causing a translational frameshift with a predicted alternate stop codon (p.F770Sfs*12). Based on internal structural assessment, this alteration eliminates most of the DIX domain, which is critical for formation of the Wnt signaling complex (Fiedler M et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Feb;108(5):1937-42). This alteration is expected to result in loss of function by premature protein truncation. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with AXIN2-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.9

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over