rs759790948

Variant names:

• chr17-65537780-G-A
• rs759790948
• NM_004655.4:c.1256C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65537780-G-A
• chr17-65537780-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000307078.10(AXIN2):​c.1256C>T​(p.Thr419Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,436,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. T419A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: AXIN2 ENST00000307078.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.869
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07888836).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307078.10. 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.1256C>T	p.Thr419Met	missense	Exon 6 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1256C>T	p.Thr419Met	missense	Exon 6 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.1256C>T	p.Thr419Met	missense	Exon 6 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1256C>T	p.Thr419Met	missense	Exon 5 of 9	ENSP00000364854.5
	AXIN2	ENST00000618960.4	TSL:5	c.1256C>T	p.Thr419Met	missense	Exon 6 of 10	ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1436592 Hom.: 1 Cov.: 37 AF XY: 0.0000112 AC XY: 8 AN XY: 711976

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.0000243 AC: 1 AN: 41226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 38542

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51368

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1099360

Other (OTH) AF: 0.0000337 AC: 2 AN: 59328

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.72	T
PhyloP100		0.87
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.21
Sift	Benign	0.37	T
Sift4G	Benign	0.23	T
Polyphen		0.53	P
Vest4		0.20
MVP		0.59
MPC		0.23
ClinPred		0.030	T
GERP RS		2.9
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs759790948; hg19: chr17-63533898; COSMIC: COSV106100397;