rs73346297

Variant names:

• chr17-65537463-G-C
• rs73346297
• NM_004655.4:c.1573C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-65537463-G-C
• chr17-65537463-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004655.4(AXIN2):​c.1573C>G​(p.Pro525Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,613,936 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P525L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0086 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (22 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.15
• Publications: 4 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: Ambry Genetics, ClinGen, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067765415).
• BP6: Variant 17-65537463-G-C is Benign according to our data. Variant chr17-65537463-G-C is described in ClinVar as Benign. ClinVar VariationId is 136483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00861 (1309/152064) while in subpopulation AFR AF = 0.0296 (1227/41506). AF 95% confidence interval is 0.0282. There are 19 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1309 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.1573C>G	p.Pro525Ala	missense	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1573C>G	p.Pro525Ala	missense	Exon 6 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.1573C>G	p.Pro525Ala	missense	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1573C>G	p.Pro525Ala	missense	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1573C>G	p.Pro525Ala	missense	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.00858 AC: 1303 AN: 151946 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00201 AC: 505 AN: 251430 AF XY: 0.00148

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000800 AC: 1170 AN: 1461872 Hom.: 22 Cov.: 35 AF XY: 0.000688 AC XY: 500 AN XY: 727244

African (AFR) AF: 0.0292 AC: 977 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112010

Other (OTH) AF: 0.00187 AC: 113 AN: 60396

GnomAD4 genome AF: 0.00861 AC: 1309 AN: 152064 Hom.: 19 Cov.: 32 AF XY: 0.00810 AC XY: 602 AN XY: 74298

African (AFR) AF: 0.0296 AC: 1227 AN: 41506

American (AMR) AF: 0.00405 AC: 62 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00109 Hom.: 2

Bravo AF: 0.00991

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Oligodontia-cancer predisposition syndrome (2)
-	-	1	AXIN2-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.43	B
Vest4		0.29
MVP		0.42
MPC		0.21
ClinPred		0.0074	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.40
Mutation Taster		=96/4	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: rs73346297; hg19: chr17-63533581;