chr17-65530080-C-T

Variant names:

• chr17-65530080-C-T
• rs140344858
• NM_004655.4:c.2428G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_004655.4(AXIN2):​c.2428G>A​(p.Asp810Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,614,174 control chromosomes in the GnomAD database, including 3 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. D810H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 5.01
• Publications: 8 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 -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-65530080-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1422755.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012767017).
• BP6: Variant 17-65530080-C-T is Benign according to our data. Variant chr17-65530080-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127945.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (175/152306) while in subpopulation AFR AF = 0.00392 (163/41568). AF 95% confidence interval is 0.00343. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 175 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.2428G>A	p.Asp810Asn	missense	Exon 11 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.2233G>A	p.Asp745Asn	missense	Exon 10 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.2428G>A	p.Asp810Asn	missense	Exon 11 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.2233G>A	p.Asp745Asn	missense	Exon 9 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.2428G>A	p.Asp810Asn	missense	Exon 11 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251282 AF XY: 0.000162

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461868 Hom.: 2 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727240

African (AFR) AF: 0.00541 AC: 181 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112002

Other (OTH) AF: 0.000397 AC: 24 AN: 60392

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74466

African (AFR) AF: 0.00392 AC: 163 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000389 Hom.: 0

Bravo AF: 0.00134

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000346 AC: 42

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	AXIN2-related disorder (1)
-	1	-	not provided (1)
-	-	1	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.84	T
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.086	T
Polyphen		0.14	B
Vest4		0.25
MVP		0.39
MPC		0.21
ClinPred		0.063	T
GERP RS		3.6
gMVP		0.35
Mutation Taster		=61/39	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: rs140344858; hg19: chr17-63526198; COSMIC: COSV61055908; COSMIC: COSV61055908;