17-65537421-C-T

Variant names:

• chr17-65537421-C-T
• rs9913621
• NM_004655.4:c.1615G>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.1615G>A​(p.Val539Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,986 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V539L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 7.42
• Publications: 11 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=0.0045544505).
• BP6: Variant 17-65537421-C-T is Benign according to our data. Variant chr17-65537421-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136484.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 = 0.0126 (1915/152106) while in subpopulation AFR AF = 0.0438 (1817/41508). AF 95% confidence interval is 0.0421. There are 47 homozygotes in GnomAd4. There are 935 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1915 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.1615G>A	p.Val539Met	missense	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1615G>A	p.Val539Met	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.1615G>A	p.Val539Met	missense	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1615G>A	p.Val539Met	missense	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1615G>A	p.Val539Met	missense	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 151988 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

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: 0.0000882

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00322 AC: 810 AN: 251370 AF XY: 0.00238

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00130 AC: 1898 AN: 1461880 Hom.: 36 Cov.: 36 AF XY: 0.00113 AC XY: 825 AN XY: 727238

African (AFR) AF: 0.0439 AC: 1471 AN: 33478

American (AMR) AF: 0.00239 AC: 107 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: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1112010

Other (OTH) AF: 0.00366 AC: 221 AN: 60396

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152106 Hom.: 47 Cov.: 32 AF XY: 0.0126 AC XY: 935 AN XY: 74350

African (AFR) AF: 0.0438 AC: 1817 AN: 41508

American (AMR) AF: 0.00451 AC: 69 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00378 Hom.: 40

Bravo AF: 0.0138

ESP6500AA AF: 0.0393 AC: 173

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00404 AC: 491

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Oligodontia-cancer predisposition syndrome (4)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.54	T
PhyloP100		7.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D
Sift4G	Benign	0.069	T
Polyphen		0.98	D
Vest4		0.56
MVP		0.77
MPC		0.67
ClinPred		0.015	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.41
Mutation Taster		=83/17	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: rs9913621; hg19: chr17-63533539; COSMIC: COSV104596717;