NM_004655.4:c.2240A>T

Variant names:

• chr17-65534077-T-A
• rs62640031
• NM_004655.4:c.2240A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004655.4(AXIN2):​c.2240A>T​(p.His747Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H747Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 NM_004655.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18519214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.2240A>T	p.His747Leu	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.2240A>T	p.His747Leu	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.2045A>T	p.His682Leu	missense_variant, splice_region_variant	Exon 8 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.2045A>T	p.His682Leu	missense_variant, splice_region_variant	Exon 9 of 10	5		ENSP00000478916.1
AXIN2	ENST00000578251.1	n.462A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.31	.;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.88	T
PhyloP100		3.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.18
Sift	Benign	0.36	T;.;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.11	.;B;B
Vest4		0.53
MutPred		0.27		Loss of solvent accessibility (P = 0.0371);.;.;
MVP		0.43
MPC		0.25
ClinPred		0.49	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.32
Mutation Taster		=92/8	polymorphism

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: rs62640031; hg19: chr17-63530195;