17-65536436-ACGGGGGGTGGTG-A

Position:

chr17-65536436-ACGGGGGGTGGTG-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_004655.4(AXIN2):c.2013_2024delCACCACCCCCCG(p.Thr672_Arg675del) variant causes a disruptive 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 (★★).

Frequency

Genomes: 𝑓 0.021 ( 119 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 110 hom. )

Consequence

AXIN2
NM_004655.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.55

Variant links:

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 links:

AXIN2 (HGNC:):

AXIN2 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.2013_2024delCACCACCCCCCG	p.Thr672_Arg675del	disruptive_inframe_deletion	8/11	ENST00000307078.10	NP_004646.3	Q9Y2T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AXIN2	ENST00000307078.10 linkuse as main transcript	c.2013_2024delCACCACCCCCCG	p.Thr672_Arg675del	disruptive_inframe_deletion	8/11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1818_1829delCACCACCCCCCG	p.Thr607_Arg610del	disruptive_inframe_deletion	6/9	1		ENSP00000364854.5	E7ES00
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1818_1829delCACCACCCCCCG	p.Thr607_Arg610del	disruptive_inframe_deletion	7/10	5		ENSP00000478916.1	E7ES00
AXIN2	ENST00000578251.1 linkuse as main transcript	n.235_246delCACCACCCCCCG		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3126

AN:

152176

Hom.:

119

Cov.:

show subpopulations

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.:

AF XY:

0.00393

AC XY:

523

AN XY:

132974

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0194

AC XY:

1447

AN XY:

74482

show subpopulations

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.:

Bravo

AF:

0.0237

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	Myriad Genetics, Inc.	Jul 09, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over