chr17-65529344-G-GA

Variant names:

• chr17-65529344-G-GA
• rs796431470
• NM_004655.4:c.*631dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004655.4(AXIN2):​c.*631dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 184,298 control chromosomes in the GnomAD database, including 95 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (93 hom., cov: 32)
  • Exomes 𝑓: 0.16 (2 hom.)
• Consequence: AXIN2 NM_004655.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.16
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0683 is higher than 0.05.

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.*631dupT		3_prime_UTR	Exon 11 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.*631dupT		3_prime_UTR	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.*631dupT		3_prime_UTR	Exon 11 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000881031.1		c.*631dupT		3_prime_UTR	Exon 11 of 11	ENSP00000551090.1
	AXIN2	ENST00000881032.1		c.*631dupT		3_prime_UTR	Exon 11 of 11	ENSP00000551091.1

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 3835 AN: 143298 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00870

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.00731

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00840

Gnomad OTH AF: 0.0288

GnomAD4 exome AF: 0.165 AC: 6753 AN: 40946 Hom.: 2 Cov.: 0 AF XY: 0.162 AC XY: 3112 AN XY: 19184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.242 AC: 467 AN: 1932

American (AMR) AF: 0.142 AC: 344 AN: 2420

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 369 AN: 2238

East Asian (EAS) AF: 0.135 AC: 655 AN: 4854

South Asian (SAS) AF: 0.119 AC: 99 AN: 830

European-Finnish (FIN) AF: 0.0414 AC: 13 AN: 314

Middle Eastern (MID) AF: 0.189 AC: 37 AN: 196

European-Non Finnish (NFE) AF: 0.168 AC: 4191 AN: 24956

Other (OTH) AF: 0.180 AC: 578 AN: 3206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0268 AC: 3849 AN: 143352 Hom.: 93 Cov.: 32 AF XY: 0.0263 AC XY: 1829 AN XY: 69440

African (AFR) AF: 0.0705 AC: 2770 AN: 39318

American (AMR) AF: 0.0136 AC: 194 AN: 14310

Ashkenazi Jewish (ASJ) AF: 0.00870 AC: 29 AN: 3334

East Asian (EAS) AF: 0.0163 AC: 81 AN: 4966

South Asian (SAS) AF: 0.00734 AC: 33 AN: 4496

European-Finnish (FIN) AF: 0.0161 AC: 138 AN: 8576

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.00840 AC: 548 AN: 65212

Other (OTH) AF: 0.0281 AC: 55 AN: 1960

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.0279

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	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: rs796431470; hg19: chr17-63525462; COSMIC: COSV61061308; COSMIC: COSV61061308;