17-65528964-A-T

Variant names:

• chr17-65528964-A-T
• rs7591
• NM_004655.4:c.*1012T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004655.4(AXIN2):​c.*1012T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 271,810 control chromosomes in the GnomAD database, including 40,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (20369 hom., cov: 33)
  • Exomes 𝑓: 0.56 (19652 hom.)
• Consequence: AXIN2 NM_004655.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00700
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.*1012T>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.*1012T>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000618960.4	c.*1012T>A		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75020 AN: 151986 Hom.: 20367 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.561 AC: 67134 AN: 119706 Hom.: 19652 Cov.: 0 AF XY: 0.564 AC XY: 32911 AN XY: 58306

African (AFR) AF: 0.250 AC: 1051 AN: 4208

American (AMR) AF: 0.551 AC: 2007 AN: 3642

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 3952 AN: 6016

East Asian (EAS) AF: 0.376 AC: 4504 AN: 11988

South Asian (SAS) AF: 0.557 AC: 3260 AN: 5852

European-Finnish (FIN) AF: 0.569 AC: 1198 AN: 2106

Middle Eastern (MID) AF: 0.522 AC: 396 AN: 758

European-Non Finnish (NFE) AF: 0.601 AC: 45737 AN: 76144

Other (OTH) AF: 0.559 AC: 5029 AN: 8992

GnomAD4 genome AF: 0.493 AC: 75023 AN: 152104 Hom.: 20369 Cov.: 33 AF XY: 0.493 AC XY: 36650 AN XY: 74344

African (AFR) AF: 0.253 AC: 10499 AN: 41500

American (AMR) AF: 0.536 AC: 8189 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2312 AN: 3472

East Asian (EAS) AF: 0.365 AC: 1887 AN: 5176

South Asian (SAS) AF: 0.566 AC: 2728 AN: 4822

European-Finnish (FIN) AF: 0.592 AC: 6252 AN: 10558

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.607 AC: 41263 AN: 67972

Other (OTH) AF: 0.509 AC: 1074 AN: 2112

Alfa AF: 0.418 Hom.: 1255

Bravo AF: 0.481

Asia WGS AF: 0.422 AC: 1470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.49
DANN	Benign	0.66
PhyloP100		-0.0070
Mutation Taster		=100/0	polymorphism (auto)

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: rs7591; hg19: chr17-63525082;