Genetic Variant AXIN2:p.His389Pro (chr17-65538237-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004655.4(AXIN2):c.1166A>C(p.His389Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H389Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.15

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:

ENSG00000266076 (HGNC:):

ENSG00000266076 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19937688).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1166A>C	p.His389Pro	missense	Exon 5 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1166A>C	p.His389Pro	missense	Exon 5 of 10	NP_001350742.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1166A>C	p.His389Pro	missense	Exon 5 of 11	ENSP00000302625.5
AXIN2	ENST00000375702.5	TSL:1	c.1166A>C	p.His389Pro	missense	Exon 4 of 9	ENSP00000364854.5
ENSG00000266076	ENST00000577662.1	TSL:2	n.*1342A>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000462418.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250806

AF XY:

0.00000737

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Benign

-0.19

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.88

PhyloP100

4.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Uncertain

0.014

Sift4G

Uncertain

0.035

Polyphen

0.0

Vest4

0.28

MutPred

0.17

Gain of glycosylation at H389 (P = 0.0264)

MVP

0.32

MPC

0.28

ClinPred

0.46

GERP RS

5.2

gMVP

0.19

Mutation Taster

=78/22

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over