rs140510381

Variant names:

• chr17-65536378-C-A
• rs140510381
• NM_004655.4:c.2083G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65536378-C-A
• chr17-65536378-C-T

Variant summary

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

The ENST00000307078.10(AXIN2):​c.2083G>T​(p.Ala695Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A695T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: AXIN2 ENST00000307078.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 2.49
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0501076).
• BP6: Variant 17-65536378-C-A is Benign according to our data. Variant chr17-65536378-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415218.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000965 (141/1461388) while in subpopulation MID AF = 0.0014 (8/5726). AF 95% confidence interval is 0.000911. There are 0 homozygotes in GnomAdExome4. There are 93 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307078.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.2083G>T	p.Ala695Ser	missense	Exon 8 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1888G>T	p.Ala630Ser	missense	Exon 7 of 10	NP_001350742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.2083G>T	p.Ala695Ser	missense	Exon 8 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1888G>T	p.Ala630Ser	missense	Exon 6 of 9	ENSP00000364854.5
	AXIN2	ENST00000618960.4	TSL:5	c.1888G>T	p.Ala630Ser	missense	Exon 7 of 10	ENSP00000478916.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000164 AC: 40 AN: 243932 AF XY: 0.000234

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: 0.0000464

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461388 Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5726

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111968

Other (OTH) AF: 0.000133 AC: 8 AN: 60376

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74502

African (AFR) AF: 0.0000240 AC: 1 AN: 41598

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Oligodontia-cancer predisposition syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	AXIN2-related disorder (1)
-	1	-	Malignant tumor of breast (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.20
Sift	Benign	0.49	T
Sift4G	Benign	0.58	T
Polyphen		0.64	P
Vest4		0.56
MVP		0.55
MPC		0.44
ClinPred		0.057	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30
Mutation Taster		=32/68	disease causing

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: rs140510381; hg19: chr17-63532496; COSMIC: COSV61055891;