rs35415678

chr17-65536399-G-Achr17-65536399-G-Cchr17-65536399-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004655.4(AXIN2):c.2062C>T(p.Leu688=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,678 control chromosomes in the GnomAD database, including 6,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L688L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1473 hom., cov: 33)
  • Exomes 𝑓: 0.060 (4681 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-65536399-G-A is Benign according to our data. Variant chr17-65536399-G-A is described in ClinVar as [Benign]. Clinvar id is 259514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65536399-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.2062C>T	p.Leu688=	synonymous_variant	8/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.2062C>T	p.Leu688=	synonymous_variant	8/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1867C>T	p.Leu623=	synonymous_variant	6/9	1
AXIN2	ENST00000618960.4	c.1867C>T	p.Leu623=	synonymous_variant	7/10	5
AXIN2	ENST00000578251.1	n.284C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16801 AN: 152144 Hom.: 1455 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0444

Gnomad OTH AF: 0.0927

GnomAD3 exomes AF: 0.0911 AC: 22294 AN: 244814 Hom.: 1722 AF XY: 0.0834 AC XY: 11087 AN XY: 132880

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.0583

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0717

GnomAD4 exome AF: 0.0595 AC: 86973 AN: 1461416 Hom.: 4681 Cov.: 33 AF XY: 0.0584 AC XY: 42421 AN XY: 727004

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.0550

Gnomad4 FIN exome AF: 0.0660

Gnomad4 NFE exome AF: 0.0429

Gnomad4 OTH exome AF: 0.0649

GnomAD4 genome AF: 0.111 AC: 16862 AN: 152262 Hom.: 1473 Cov.: 33 AF XY: 0.114 AC XY: 8505 AN XY: 74468

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.0585

Gnomad4 FIN AF: 0.0724

Gnomad4 NFE AF: 0.0444

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0667 Hom.: 268

Bravo AF: 0.120

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0440

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Oligodontia-cancer predisposition syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16432638, 18790474) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The c.2062C>T in AXIN2 gene is a synonymous change that involves a conserved nucleotide. 5/5 splice-site tools in Alamut predict this variant not to have an impact on normal splicing. The variant is present in the control population dataset of ExAC at an allele frequency of 9%. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.014%, suggesting that it is a benign polymorphism. Classification information about the variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	6.4
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35415678; hg19: chr17-63532517; COSMIC: COSV61056020; COSMIC: COSV61056020;