rs749012756

Variant names:

• chr17-65537621-T-C
• rs749012756
• NM_004655.4:c.1415A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-65537621-T-C
• chr17-65537621-T-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_004655.4(AXIN2):​c.1415A>G​(p.His472Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,442,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H472Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.512
• Publications: 0 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: Ambry Genetics, ClinGen, 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08338153).
• BP6: Variant 17-65537621-T-C is Benign according to our data. Variant chr17-65537621-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581265.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004655.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1415A>G	p.His472Arg	missense	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1415A>G	p.His472Arg	missense	Exon 6 of 10	NP_001350742.1	E7ES00

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1415A>G	p.His472Arg	missense	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1415A>G	p.His472Arg	missense	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1415A>G	p.His472Arg	missense	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 215426 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1442144 Hom.: 0 Cov.: 38 AF XY: 0.00000978 AC XY: 7 AN XY: 716014

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 41126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.00 AC: 0 AN: 85246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1104612

Other (OTH) AF: 0.0000167 AC: 1 AN: 59862

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000832 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.51
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.070
Sift	Benign	0.35	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.21		Gain of methylation at H472 (P = 0.0399)
MVP		0.51
MPC		0.22
ClinPred		0.14	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.096
Mutation Taster		=86/14	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: rs749012756; hg19: chr17-63533739;