NM_004655.4:c.2272G>A

Variant names:

• chr17-65534045-C-T
• rs145007501
• NM_004655.4:c.2272G>A

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.2272G>A​(p.Ala758Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,614,216 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict 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. A758V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:1
• Conservation: PhyloP100: -0.148
• Publications: 19 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=0.005823612).
• BP6: Variant 17-65534045-C-T is Benign according to our data. Variant chr17-65534045-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127943.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152336) while in subpopulation NFE AF = 0.00326 (222/68030). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 262 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.2272G>A	p.Ala758Thr	missense	Exon 10 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.2077G>A	p.Ala693Thr	missense	Exon 9 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.2272G>A	p.Ala758Thr	missense	Exon 10 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.2077G>A	p.Ala693Thr	missense	Exon 8 of 9	ENSP00000364854.5
	AXIN2	ENST00000881031.1		c.2272G>A	p.Ala758Thr	missense	Exon 10 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00192 AC: 484 AN: 251486 AF XY: 0.00181

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00270 AC: 3942 AN: 1461880 Hom.: 9 Cov.: 33 AF XY: 0.00261 AC XY: 1897 AN XY: 727242

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00335 AC: 3723 AN: 1112008

Other (OTH) AF: 0.00187 AC: 113 AN: 60394

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74494

African (AFR) AF: 0.000529 AC: 22 AN: 41578

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00326 AC: 222 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00251 Hom.: 2

Bravo AF: 0.00176

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00240 AC: 291

EpiCase AF: 0.00267

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (7)
-	1	3	not specified (4)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	-	3	Oligodontia-cancer predisposition syndrome (3)
-	-	1	AXIN2-related disorder (1)
-	-	1	Colorectal cancer;C4082304:Oligodontia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.15
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.051
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.0040	B
Vest4		0.051
MVP		0.51
MPC		0.17
ClinPred		0.0068	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16
Mutation Taster		=94/6	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: rs145007501; hg19: chr17-63530163; COSMIC: COSV61057162; COSMIC: COSV61057162;