NM_004655.4:c.1985T>C

Variant names:

• chr17-65536476-A-G
• rs142476324
• NM_004655.4:c.1985T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004655.4(AXIN2):​c.1985T>C​(p.Leu662Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,613,924 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. L662V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 3.80
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01240769).
• BP6: Variant 17-65536476-A-G is Benign according to our data. Variant chr17-65536476-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127939.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000886 (135/152362) while in subpopulation NFE AF = 0.00153 (104/68036). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 135 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.1985T>C	p.Leu662Pro	missense	Exon 8 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1790T>C	p.Leu597Pro	missense	Exon 7 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.1985T>C	p.Leu662Pro	missense	Exon 8 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1790T>C	p.Leu597Pro	missense	Exon 6 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1985T>C	p.Leu662Pro	missense	Exon 8 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00102 AC: 251 AN: 245612 AF XY: 0.00127

Gnomad AFR exome AF: 0.000381

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00124 AC: 1809 AN: 1461562 Hom.: 5 Cov.: 33 AF XY: 0.00131 AC XY: 954 AN XY: 727076

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86258

European-Finnish (FIN) AF: 0.0000753 AC: 4 AN: 53134

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00142 AC: 1580 AN: 1111980

Other (OTH) AF: 0.00123 AC: 74 AN: 60384

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74506

African (AFR) AF: 0.000361 AC: 15 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	not provided (7)
-	1	4	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Oligodontia-cancer predisposition syndrome (2)
-	-	1	AXIN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.17
Sift	Benign	0.40	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	B
Vest4		0.36
MVP		0.29
MPC		0.29
ClinPred		0.017	T
GERP RS		5.4
gMVP		0.16
Mutation Taster		=91/9	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: rs142476324; hg19: chr17-63532594; COSMIC: COSV104596755;