rs138287857

Variant names:

• chr17-65536410-G-A
• rs138287857
• NM_004655.4:c.2051C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65536410-G-A
• chr17-65536410-G-C
• chr17-65536410-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004655.4(AXIN2):​c.2051C>T​(p.Ala684Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,800 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A684T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:13
• Conservation: PhyloP100: 7.55
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010069042).
• BP6: Variant 17-65536410-G-A is Benign according to our data. Variant chr17-65536410-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127941.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00108 (165/152358) while in subpopulation NFE AF = 0.00156 (106/68028). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 165 AD gene.

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.2051C>T	p.Ala684Val	missense	Exon 8 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1856C>T	p.Ala619Val	missense	Exon 7 of 10	NP_001350742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.2051C>T	p.Ala684Val	missense	Exon 8 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1856C>T	p.Ala619Val	missense	Exon 6 of 9	ENSP00000364854.5
	AXIN2	ENST00000881031.1		c.2051C>T	p.Ala684Val	missense	Exon 8 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00160 AC: 392 AN: 245102 AF XY: 0.00170

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00849

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000836

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00300

GnomAD4 exome AF: 0.00177 AC: 2588 AN: 1461442 Hom.: 6 Cov.: 33 AF XY: 0.00170 AC XY: 1236 AN XY: 727010

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000336 AC: 15 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 236 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86230

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53094

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00193 AC: 2141 AN: 1111966

Other (OTH) AF: 0.00172 AC: 104 AN: 60388

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000953 AC XY: 71 AN XY: 74516

African (AFR) AF: 0.000168 AC: 7 AN: 41598

American (AMR) AF: 0.000588 AC: 9 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00180 AC: 218

EpiCase AF: 0.00164

EpiControl AF: 0.00172

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Oligodontia-cancer predisposition syndrome (4)
-	1	2	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
1	-	-	Aganglionic megacolon (1)
-	-	1	AXIN2-related disorder (1)
-	-	1	Colorectal cancer (1)
-	-	1	Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.58	T
PhyloP100		7.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.10	T
Polyphen		0.92	P
Vest4		0.55
MVP		0.79
MPC		0.41
ClinPred		0.045	T
GERP RS		4.4
gMVP		0.40
Mutation Taster		=79/21	polymorphism

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: rs138287857; hg19: chr17-63532528; COSMIC: COSV61057901; COSMIC: COSV61057901;