rs151279728

Positions:

• chr17-65536436-ACGGGGGGTGGTG-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_004655.4(AXIN2):​c.2013_2024del​(p.Thr672_Arg675del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00393 in 1,613,670 control chromosomes in the GnomAD database, including 229 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R671R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (119 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (110 hom.)
• Consequence: AXIN2 NM_004655.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.55

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004655.4.
• BP6: Variant 17-65536436-ACGGGGGGTGGTG-A is Benign according to our data. Variant chr17-65536436-ACGGGGGGTGGTG-A is described in ClinVar as [Benign]. Clinvar id is 182018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65536436-ACGGGGGGTGGTG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.2013_2024del	p.Thr672_Arg675del	inframe_deletion	8/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.2013_2024del	p.Thr672_Arg675del	inframe_deletion	8/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1818_1829del	p.Thr607_Arg610del	inframe_deletion	6/9	1
AXIN2	ENST00000618960.4	c.1818_1829del	p.Thr607_Arg610del	inframe_deletion	7/10	5
AXIN2	ENST00000578251.1	n.235_246del		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3126 AN: 152176 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00554 AC: 1355 AN: 244704 Hom.: 44 AF XY: 0.00393 AC XY: 523 AN XY: 132974

Gnomad AFR exome AF: 0.0754

Gnomad AMR exome AF: 0.00360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000304

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00220 AC: 3214 AN: 1461376 Hom.: 110 AF XY: 0.00190 AC XY: 1379 AN XY: 726986

Gnomad4 AFR exome AF: 0.0750

Gnomad4 AMR exome AF: 0.00383

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.0206 AC: 3135 AN: 152294 Hom.: 119 Cov.: 33 AF XY: 0.0194 AC XY: 1447 AN XY: 74482

Gnomad4 AFR AF: 0.0720

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0112 Hom.: 7

Bravo AF: 0.0237

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2021	Variant summary: AXIN2 c.2013_2024del12 (p.Thr672_Arg675del) results in an in-frame deletion that is predicted to remove 4 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0055 in 244704 control chromosomes, predominantly at a frequency of 0.075 within the African or African-American subpopulation in the gnomAD database, including 44 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 528-fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. A co-occurrence with a pathogenic variant has been reported (PMS2 c.2186_2187delTC, p.Leu729GlnfsX6; Internal testing), providing further supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2021	- -

Oligodontia-cancer predisposition syndrome Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2018	This variant is associated with the following publications: (PMID: 26514524) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2018

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151279728; hg19: chr17-63532554;