17-65538420-C-A

Variant names:

• chr17-65538420-C-A
• rs4541111
• NM_004655.4:c.1060-77G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004655.4(AXIN2):​c.1060-77G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,587,454 control chromosomes in the GnomAD database, including 188,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13643 hom., cov: 32)
  • Exomes 𝑓: 0.49 (174363 hom.)
• Consequence: AXIN2 NM_004655.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• oligodontia-cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000266076 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-65538420-C-A is Benign according to our data. Variant chr17-65538420-C-A is described in ClinVar as Benign. ClinVar VariationId is 1239471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1060-77G>T		intron_variant	Intron 4 of 10	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1060-77G>T		intron_variant	Intron 4 of 10	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1060-77G>T		intron_variant	Intron 3 of 8	1		ENSP00000364854.5
ENSG00000266076	ENST00000577662.1	n.*1236-77G>T		intron_variant	Intron 6 of 6	2		ENSP00000462418.1
AXIN2	ENST00000618960.4	c.1060-77G>T		intron_variant	Intron 4 of 9	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60903 AN: 151886 Hom.: 13645 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.488 AC: 700706 AN: 1435450 Hom.: 174363 AF XY: 0.486 AC XY: 346720 AN XY: 713388

African (AFR) AF: 0.189 AC: 6214 AN: 32882

American (AMR) AF: 0.507 AC: 22153 AN: 43706

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11050 AN: 25364

East Asian (EAS) AF: 0.313 AC: 12346 AN: 39392

South Asian (SAS) AF: 0.451 AC: 38103 AN: 84410

European-Finnish (FIN) AF: 0.522 AC: 27316 AN: 52354

Middle Eastern (MID) AF: 0.350 AC: 1778 AN: 5074

European-Non Finnish (NFE) AF: 0.508 AC: 554932 AN: 1092916

Other (OTH) AF: 0.452 AC: 26814 AN: 59352

GnomAD4 genome AF: 0.401 AC: 60905 AN: 152004 Hom.: 13643 Cov.: 32 AF XY: 0.400 AC XY: 29695 AN XY: 74268

African (AFR) AF: 0.196 AC: 8115 AN: 41486

American (AMR) AF: 0.443 AC: 6764 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1485 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1592 AN: 5146

South Asian (SAS) AF: 0.443 AC: 2137 AN: 4828

European-Finnish (FIN) AF: 0.517 AC: 5453 AN: 10552

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33825 AN: 67946

Other (OTH) AF: 0.387 AC: 815 AN: 2106

Alfa AF: 0.466 Hom.: 70595

Bravo AF: 0.389

Asia WGS AF: 0.337 AC: 1175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.6
DANN	Benign	0.72
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4541111; hg19: chr17-63534538; COSMIC: COSV61057494; COSMIC: COSV61057494;