17-65536431-T-G

Variant names:

• chr17-65536431-T-G
• rs1555577107
• NM_004655.4:c.2030A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004655.4(AXIN2):​c.2030A>C​(p.His677Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H677Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

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.2030A>C	p.His677Pro	missense	Exon 8 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1835A>C	p.His612Pro	missense	Exon 7 of 10	NP_001350742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.2030A>C	p.His677Pro	missense	Exon 8 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1835A>C	p.His612Pro	missense	Exon 6 of 9	ENSP00000364854.5
	AXIN2	ENST00000618960.4	TSL:5	c.1835A>C	p.His612Pro	missense	Exon 7 of 10	ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.18	T
PhyloP100		5.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.39		Gain of glycosylation at H677 (P = 0.0333)
MVP		0.72
MPC		0.89
ClinPred		0.98	D
GERP RS		5.4
gMVP		0.46
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555577107; hg19: chr17-63532549;