17-65537614-ATGGTGGTGG-ATGGTGGTGGTGGTGG

Variant names:

• chr17-65537614-A-ATGGTGG
• rs570443161
• NM_004655.4:c.1416_1421dupCCACCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004655.4(AXIN2):​c.1416_1421dupCCACCA​(p.His473_His474dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,428,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H474H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: AXIN2 NM_004655.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.584
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 17-65537614-A-ATGGTGG is Benign according to our data. Variant chr17-65537614-A-ATGGTGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239988.
• BS2: High AC in GnomAdExome4 at 15 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.1416_1421dupCCACCA	p.His473_His474dup	disruptive_inframe_insertion	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1416_1421dupCCACCA	p.His473_His474dup	disruptive_inframe_insertion	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.1416_1421dupCCACCA	p.His473_His474dup	disruptive_inframe_insertion	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1416_1421dupCCACCA	p.His473_His474dup	disruptive_inframe_insertion	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1416_1421dupCCACCA	p.His473_His474dup	disruptive_inframe_insertion	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000479 AC: 1 AN: 208906 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1428898 Hom.: 0 Cov.: 37 AF XY: 0.00000986 AC XY: 7 AN XY: 709648

African (AFR) AF: 0.0000302 AC: 1 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 41246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39166

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000915 AC: 10 AN: 1093076

Other (OTH) AF: 0.00 AC: 0 AN: 59242

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	not provided (1)
-	1	-	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs570443161; hg19: chr17-63533732;