rs7219582

Positions:

• chr17-65537305-C-A
• chr17-65537305-C-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.1712+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,254 control chromosomes in the GnomAD database, including 11,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1939 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9750 hom.)
• Consequence: AXIN2 NM_004655.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.07

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=-0.93).
• BP6: Variant 17-65537305-C-A is Benign according to our data. Variant chr17-65537305-C-A is described in ClinVar as [Benign]. Clinvar id is 259512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65537305-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1712+19G>T		intron_variant		ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1712+19G>T		intron_variant		1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.1712+19G>T		intron_variant		1		ENSP00000364854
AXIN2	ENST00000618960.4	c.1712+19G>T		intron_variant		5		ENSP00000478916

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22342 AN: 152002 Hom.: 1934 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.119 AC: 29684 AN: 249130 Hom.: 2083 AF XY: 0.120 AC XY: 16133 AN XY: 134854

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0796

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.0662

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.110 AC: 160860 AN: 1461134 Hom.: 9750 Cov.: 35 AF XY: 0.112 AC XY: 81634 AN XY: 726898

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.0845

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.147 AC: 22370 AN: 152120 Hom.: 1939 Cov.: 32 AF XY: 0.145 AC XY: 10747 AN XY: 74352

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.0574

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.166

Alfa AF: 0.136 Hom.: 297

Bravo AF: 0.153

Asia WGS AF: 0.133 AC: 463 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	Variant summary: The variant of interest is located at a non-conserved intronic position, not widely known to affect splicing, with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 14771/121216 (1/8 including 1069 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic AXIN2 variant of 1/7037. The variant of interest has been reported in affected individuals via publications with a classification of "polymorphism." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.022
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs7219582; hg19: chr17-63533423;