NM_004655.4:c.1209G>A

Variant names:

• chr17-65537827-C-T
• rs774657791
• NM_004655.4:c.1209G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004655.4(AXIN2):​c.1209G>A​(p.Glu403Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000427 in 1,405,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-65537827-C-T is Benign according to our data. Variant chr17-65537827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2566129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1209G>A	p.Glu403Glu	synonymous_variant	Exon 6 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1209G>A	p.Glu403Glu	synonymous_variant	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1209G>A	p.Glu403Glu	synonymous_variant	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1209G>A	p.Glu403Glu	synonymous_variant	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1405198 Hom.: 0 Cov.: 36 AF XY: 0.00000722 AC XY: 5 AN XY: 692752

African (AFR) AF: 0.0000314 AC: 1 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 36838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23248

East Asian (EAS) AF: 0.00 AC: 0 AN: 38458

South Asian (SAS) AF: 0.00 AC: 0 AN: 77442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1083650

Other (OTH) AF: 0.0000173 AC: 1 AN: 57828

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Benign:1

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 15, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.9
DANN	Benign	0.62
PhyloP100		1.1

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: rs774657791; hg19: chr17-63533945;