17-65537786-G-C

Variant names:

• chr17-65537786-G-C
• rs201460658
• NM_004655.4:c.1250C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004655.4(AXIN2):​c.1250C>G​(p.Ala417Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A417V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09024069).
• BP6: Variant 17-65537786-G-C is Benign according to our data. Variant chr17-65537786-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3224356.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1250C>G	p.Ala417Gly	missense_variant	Exon 6 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1250C>G	p.Ala417Gly	missense_variant	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1250C>G	p.Ala417Gly	missense_variant	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1250C>G	p.Ala417Gly	missense_variant	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434534 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 710880

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.00 AC: 0 AN: 40752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.00 AC: 0 AN: 82280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098674

Other (OTH) AF: 0.00 AC: 0 AN: 59224

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Dec 08, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.9
DANN	Benign	0.86
DEOGEN2	Benign	0.26	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	.;T;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.090	T;T;T
MetaSVM	Benign	-0.82	T
PhyloP100		0.30
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.64	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.27	T;.;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.098
MutPred		0.075		Loss of glycosylation at S413 (P = 0.2476);Loss of glycosylation at S413 (P = 0.2476);Loss of glycosylation at S413 (P = 0.2476);
MVP		0.48
MPC		0.18
ClinPred		0.053	T
GERP RS		-0.27
gMVP		0.13
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201460658; hg19: chr17-63533904;