rs2240308

Variant names:

• chr17-65558473-G-A
• rs2240308
• NM_004655.4:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65558473-G-A
• chr17-65558473-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004655.4(AXIN2):​c.148C>T​(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,605,836 control chromosomes in the GnomAD database, including 201,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (14296 hom., cov: 32)
  • Exomes 𝑓: 0.50 (187519 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.14
• Publications: 118 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

ENSG00000266076 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7431378E-4).
• BP6: Variant 17-65558473-G-A is Benign according to our data. Variant chr17-65558473-G-A is described in ClinVar as Benign. ClinVar VariationId is 259511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

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.148C>T	p.Pro50Ser	missense	Exon 2 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.148C>T	p.Pro50Ser	missense	Exon 2 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.148C>T	p.Pro50Ser	missense	Exon 2 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.148C>T	p.Pro50Ser	missense	Exon 1 of 9	ENSP00000364854.5	E7ES00
	ENSG00000266076	ENST00000577662.1	TSL:2	n.*324C>T		non_coding_transcript_exon	Exon 4 of 7	ENSP00000462418.1	J3KSC3

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60184 AN: 151988 Hom.: 14295 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.474 AC: 117123 AN: 247006 AF XY: 0.479

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.325

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.502 AC: 729689 AN: 1453730 Hom.: 187519 Cov.: 79 AF XY: 0.500 AC XY: 361223 AN XY: 721970

African (AFR) AF: 0.111 AC: 3709 AN: 33340

American (AMR) AF: 0.537 AC: 23772 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12130 AN: 25552

East Asian (EAS) AF: 0.316 AC: 12507 AN: 39550

South Asian (SAS) AF: 0.468 AC: 39964 AN: 85478

European-Finnish (FIN) AF: 0.514 AC: 27306 AN: 53138

Middle Eastern (MID) AF: 0.366 AC: 2096 AN: 5722

European-Non Finnish (NFE) AF: 0.524 AC: 579872 AN: 1106654

Other (OTH) AF: 0.472 AC: 28333 AN: 59992

GnomAD4 genome AF: 0.396 AC: 60181 AN: 152106 Hom.: 14296 Cov.: 32 AF XY: 0.396 AC XY: 29414 AN XY: 74352

African (AFR) AF: 0.127 AC: 5294 AN: 41532

American (AMR) AF: 0.474 AC: 7247 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1632 AN: 3470

East Asian (EAS) AF: 0.326 AC: 1680 AN: 5146

South Asian (SAS) AF: 0.465 AC: 2240 AN: 4816

European-Finnish (FIN) AF: 0.495 AC: 5246 AN: 10592

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35417 AN: 67952

Other (OTH) AF: 0.386 AC: 815 AN: 2110

Alfa AF: 0.492 Hom.: 69630

Bravo AF: 0.385

TwinsUK AF: 0.520 AC: 1929

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.135 AC: 596

ESP6500EA AF: 0.528 AC: 4539

ExAC AF: 0.469 AC: 56987

Asia WGS AF: 0.366 AC: 1274 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Oligodontia-cancer predisposition syndrome (5)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.68
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.00017	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Benign	0.37	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.18
ClinPred		0.0076	T
GERP RS		2.8
PromoterAI		0.015	Neutral
gMVP		0.17
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2240308; hg19: chr17-63554591; COSMIC: COSV61057354;