rs760667639

chr17-65537842-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004655.4(AXIN2):c.1201-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,543,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: AXIN2 NM_004655.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003005
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0880

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-65537842-G-A is Benign according to our data. Variant chr17-65537842-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380265.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1201-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1201-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1201-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
AXIN2	ENST00000618960.4	c.1201-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 4 AN: 165938 Hom.: 0 AF XY: 0.0000224 AC XY: 2 AN XY: 89410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000696

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1391340 Hom.: 0 Cov.: 37 AF XY: 0.0000205 AC XY: 14 AN XY: 684480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000523

Gnomad4 SAS exome AF: 0.0000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000928

Gnomad4 OTH exome AF: 0.0000524

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74302

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Oligodontia-cancer predisposition syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.18
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.060
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: rs760667639; hg19: chr17-63533960;