17-65537814-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E408D) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 3.62

Publications

2 publications found

Variant links:

COSMIC-nc: COSV61061853

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10790479).

BP6

Variant 17-65537814-C-T is Benign according to our data. Variant chr17-65537814-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408784.

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004655.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1222G>A	p.Glu408Lys	missense	Exon 6 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1222G>A	p.Glu408Lys	missense	Exon 6 of 10	NP_001350742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1222G>A	p.Glu408Lys	missense	Exon 6 of 11	ENSP00000302625.5
AXIN2	ENST00000375702.5	TSL:1	c.1222G>A	p.Glu408Lys	missense	Exon 5 of 9	ENSP00000364854.5
AXIN2	ENST00000881031.1		c.1222G>A	p.Glu408Lys	missense	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000671

AC:

AN:

193720

AF XY:

0.0000474

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000233

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1420528

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

702456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32208

American (AMR)

AF:

0.000287

AC:

AN:

38374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24042

East Asian (EAS)

AF:

0.00

AC:

AN:

38728

South Asian (SAS)

AF:

0.00

AC:

AN:

79714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00000641

AC:

AN:

1092364

Other (OTH)

AF:

0.00

AC:

AN:

58496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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

AF:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000421

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000579

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Oligodontia-cancer predisposition syndrome (2)

AXIN2-related disorder (1)

Colorectal cancer (1)

Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.45

PhyloP100

3.6

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.8

REVEL

Benign

0.25

Sift

Benign

0.051

Sift4G

Benign

0.21

Polyphen

0.38

Vest4

0.31

MutPred

0.23

Gain of ubiquitination at E408 (P = 9e-04)

MVP

0.69

MPC

0.25

ClinPred

0.097

GERP RS

5.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

gMVP

0.22

Mutation Taster

=84/16

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over