17-65528964-A-T

Position:

• chr17-65528964-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-65528964-A-T is Benign according to our data. Variant chr17-65528964-A-T is described in ClinVar as [Benign]. Clinvar id is 324630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.*1012T>A		3_prime_UTR_variant	11/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078	c.*1012T>A		3_prime_UTR_variant	11/11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000618960	c.*1012T>A		3_prime_UTR_variant	10/10	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

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.551

Gnomad4 ASJ exome AF: 0.657

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.569

Gnomad4 NFE exome AF: 0.601

Gnomad4 OTH exome AF: 0.559

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

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.666

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.566

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.509

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.49
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs7591; hg19: chr17-63525082;