rs772888193

chr17-65534068-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004655.4(AXIN2):c.2249C>T(p.Pro750Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,882 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P750S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.34

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15960848).
• BS2: High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.2249C>T	p.Pro750Leu	missense_variant	10/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.2249C>T	p.Pro750Leu	missense_variant	10/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.2054C>T	p.Pro685Leu	missense_variant	8/9	1
AXIN2	ENST00000618960.4	c.2054C>T	p.Pro685Leu	missense_variant	9/10	5
AXIN2	ENST00000578251.1	n.471C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251486 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 750 of the AXIN2 protein (p.Pro750Leu). This variant is present in population databases (rs772888193, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 464601). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Colorectal cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2022

The p.P750L variant (also known as c.2249C>T), located in coding exon 9 of the AXIN2 gene, results from a C to T substitution at nucleotide position 2249. The proline at codon 750 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Benign	0.97
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;.;N
REVEL	Benign	0.12
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.65	.;P;P
Vest4		0.49
MutPred		0.29		Loss of ubiquitination at K751 (P = 0.0376);.;.;
MVP		0.56
MPC		0.35
ClinPred		0.12	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.37

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: rs772888193; hg19: chr17-63530186;