17-65529667-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_004655.4(AXIN2):c.*309C>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 0.00893 in 455,118 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (58 hom.)
• Consequence: AXIN2 NM_004655.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.50

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-65529667-G-T is Benign according to our data. Variant chr17-65529667-G-T is described in ClinVar as [Benign]. Clinvar id is 324639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00563 (857/152262) while in subpopulation SAS AF= 0.0365 (176/4822). AF 95% confidence interval is 0.0321. There are 8 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 857 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.*309C>A		3_prime_UTR_variant	11/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.*309C>A		3_prime_UTR_variant	11/11	1	NM_004655.4	P1
AXIN2	ENST00000618960.4	c.*309C>A		3_prime_UTR_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 857 AN: 152144 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.00745

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.0106 AC: 3205 AN: 302856 Hom.: 58 Cov.: 3 AF XY: 0.0130 AC XY: 2070 AN XY: 158692

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000962

Gnomad4 SAS exome AF: 0.0406

Gnomad4 FIN exome AF: 0.00811

Gnomad4 NFE exome AF: 0.00637

Gnomad4 OTH exome AF: 0.00814

GnomAD4 genome AF: 0.00563 AC: 857 AN: 152262 Hom.: 8 Cov.: 33 AF XY: 0.00643 AC XY: 479 AN XY: 74454

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.00745

Gnomad4 NFE AF: 0.00637

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00540 Hom.: 0

Bravo AF: 0.00439

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.88

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: rs192185171; hg19: chr17-63525785;