rs2240307

Variant names:

• chr17-65558189-A-G
• rs2240307
• NM_004655.4:c.432T>C
• AXIN2 p.Ile144Ile

Your query was ambiguous. Multiple possible variants found:

• chr17-65558189-A-G
• chr17-65558189-A-C
• chr17-65558189-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004655.4(AXIN2):​c.432T>C​(p.Ile144Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,613,946 control chromosomes in the GnomAD database, including 1,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (317 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1183 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.117
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000266076 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-65558189-A-G is Benign according to our data. Variant chr17-65558189-A-G is described in ClinVar as Benign. ClinVar VariationId is 259515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.117 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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.432T>C	p.Ile144Ile	synonymous	Exon 2 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.432T>C	p.Ile144Ile	synonymous	Exon 2 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.432T>C	p.Ile144Ile	synonymous	Exon 2 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.432T>C	p.Ile144Ile	synonymous	Exon 1 of 9	ENSP00000364854.5	E7ES00
	ENSG00000266076	ENST00000577662.1	TSL:2	n.*608T>C		non_coding_transcript_exon	Exon 4 of 7	ENSP00000462418.1	J3KSC3

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6600 AN: 151936 Hom.: 307 Cov.: 32

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00562

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0445 AC: 11190 AN: 251492 AF XY: 0.0398

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0177 AC: 25866 AN: 1461892 Hom.: 1183 Cov.: 31 AF XY: 0.0174 AC XY: 12688 AN XY: 727248

African (AFR) AF: 0.0759 AC: 2541 AN: 33480

American (AMR) AF: 0.118 AC: 5278 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00738 AC: 193 AN: 26136

East Asian (EAS) AF: 0.166 AC: 6607 AN: 39700

South Asian (SAS) AF: 0.0398 AC: 3435 AN: 86258

European-Finnish (FIN) AF: 0.0295 AC: 1575 AN: 53418

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.00436 AC: 4849 AN: 1112012

Other (OTH) AF: 0.0216 AC: 1303 AN: 60396

GnomAD4 genome AF: 0.0436 AC: 6637 AN: 152054 Hom.: 317 Cov.: 32 AF XY: 0.0490 AC XY: 3641 AN XY: 74306

African (AFR) AF: 0.0734 AC: 3042 AN: 41462

American (AMR) AF: 0.111 AC: 1689 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.152 AC: 787 AN: 5170

South Asian (SAS) AF: 0.0482 AC: 231 AN: 4794

European-Finnish (FIN) AF: 0.0372 AC: 394 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00562 AC: 382 AN: 67968

Other (OTH) AF: 0.0374 AC: 79 AN: 2110

Alfa AF: 0.0190 Hom.: 198

Bravo AF: 0.0492

Asia WGS AF: 0.0970 AC: 337 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	5	Oligodontia-cancer predisposition syndrome (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2240307;

hg19: chr17-63554307;

COSMIC: COSV61056425;