17-65536321-G-C

Variant names:

• chr17-65536321-G-C
• rs148765149
• NM_004655.4:c.2140C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004655.4(AXIN2):​c.2140C>G​(p.Arg714Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R714W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense, splice_region
• Scores: Splicing: ADA: 0.08486
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.729
• 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: Ambry Genetics, ClinGen, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2140C>G	p.Arg714Gly	missense splice_region	Exon 8 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1945C>G	p.Arg649Gly	missense splice_region	Exon 7 of 10	NP_001350742.1	E7ES00

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.2140C>G	p.Arg714Gly	missense splice_region	Exon 8 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1945C>G	p.Arg649Gly	missense splice_region	Exon 6 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.2140C>G	p.Arg714Gly	missense splice_region	Exon 8 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456454 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724120

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 43806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110232

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.18	T
PhyloP100		0.73
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.66
MutPred		0.35		Loss of helix (P = 0.0068)
MVP		0.57
MPC		0.82
ClinPred		0.96	D
GERP RS		3.4
gMVP		0.56
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.085
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.040		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: rs148765149; hg19: chr17-63532439;