NM_004655.4:c.1413_1421delCCACCACCA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP6BS2

The NM_004655.4(AXIN2):c.1413_1421delCCACCACCA(p.His472_His474del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,428,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H471H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 3.25

Publications

5 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 17-65537614-ATGGTGGTGG-A is Benign according to our data. Variant chr17-65537614-ATGGTGGTGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 658132.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4 link	c.1413_1421delCCACCACCA	p.His472_His474del	disruptive_inframe_deletion	Exon 6 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.1413_1421delCCACCACCA	p.His472_His474del	disruptive_inframe_deletion	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 link	c.1413_1421delCCACCACCA	p.His472_His474del	disruptive_inframe_deletion	Exon 5 of 9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 link	c.1413_1421delCCACCACCA	p.His472_His474del	disruptive_inframe_deletion	Exon 6 of 10	5		ENSP00000478916.1	E7ES00

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000479

AC:

AN:

208906

AF XY:

0.00000887

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:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000350

AC:

AN:

1428898

Hom.:

AF XY:

0.00000423

AC XY:

AN XY:

709648

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33162

American (AMR)

AF:

0.00

AC:

AN:

41246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25428

East Asian (EAS)

AF:

0.00

AC:

AN:

39166

South Asian (SAS)

AF:

0.00

AC:

AN:

84204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

0.00000457

AC:

AN:

1093076

Other (OTH)

AF:

0.00

AC:

AN:

59242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome

Uncertain:1

Aug 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 658132). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant, c.1413_1421del, results in the deletion of 3 amino acid(s) of the AXIN2 protein (p.His472_His474del), but otherwise preserves the integrity of the reading frame. -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 15, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over