chr17-65538272-C-G

Variant names:

• chr17-65538272-C-G
• rs1060504480
• NM_004655.4:c.1131G>C

Variant summary

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

The NM_004655.4(AXIN2):​c.1131G>C​(p.Arg377Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171
• 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

ENSG00000266076 (HGNC:):

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1131G>C	p.Arg377Ser	missense	Exon 5 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1131G>C	p.Arg377Ser	missense	Exon 5 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.1131G>C	p.Arg377Ser	missense	Exon 5 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1131G>C	p.Arg377Ser	missense	Exon 4 of 9	ENSP00000364854.5
	ENSG00000266076	ENST00000577662.1	TSL:2	n.*1307G>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000462418.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.38	D
PhyloP100		0.17
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.044	D
Polyphen		0.88	P
Vest4		0.74
MutPred		0.27		Gain of phosphorylation at R377 (P = 0.0186)
MVP		0.76
MPC		0.32
ClinPred		0.97	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.46
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs1060504480; hg19: chr17-63534390; COSMIC: COSV61062074;