rs752881223

Positions:

• chr17-65558307-A-C
• chr17-65558307-A-G
• chr17-65558307-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000307078.10(AXIN2):​c.314T>G​(p.Val105Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V105A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 ENST00000307078.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-65558307-A-C is Pathogenic according to our data. Variant chr17-65558307-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 217441.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.314T>G	p.Val105Gly	missense_variant	2/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.314T>G	p.Val105Gly	missense_variant	2/11	1	NM_004655.4	ENSP00000302625	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Non-syndromic oligodontia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Prosthodontics, Peking University School and Hospital of Stomatology

-

The proband was an 8-year-old male with a normal appearance. Clinical and radiographic examinations revealed that, in addition to retained deciduous teeth, the patient was missing a total of seven permanent teeth excluding third molars, all of them premolars. The incisors, canines, first molars and second molars were normal. No tooth germ for third molars was detected. Considering his young age, a diagnosis could not yet be made in relation to the lack of third molars. The proband’s facial features, skin, hair and nails appeared normal. Also, he reported normal sweating and lachrymal secretion and denied intolerance to heat, or susceptibility to respiratory tract infections. His parents’ dentition was normal, and they reported no family history of tooth agenesis, ectodermal abnormalities or cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.30	.;.;T;T;T;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	.;T;T;.;D;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N;.;.;N;.;.;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.23	T;.;.;T;.;.;.;T
Sift4G	Benign	0.16	T;D;T;T;.;.;.;.
Polyphen		0.99	.;.;D;D;.;.;.;.
Vest4		0.76
MutPred		0.44		Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);Loss of stability (P = 0.0039);
MVP		0.39
MPC		0.47
ClinPred		0.91	D
GERP RS		4.9
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs752881223; hg19: chr17-63554425;