rs9914661

Variant names:

• chr17-65537653-G-A
• rs9914661
• NM_004655.4:c.1383C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65537653-G-A
• chr17-65537653-G-C
• chr17-65537653-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004655.4(AXIN2):​c.1383C>T​(p.Ser461Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,568,738 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.770
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 17-65537653-G-A is Benign according to our data. Variant chr17-65537653-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1921/152138) while in subpopulation AFR AF = 0.0438 (1821/41542). AF 95% confidence interval is 0.0422. There are 47 homozygotes in GnomAd4. There are 937 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1921 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.1383C>T	p.Ser461Ser	synonymous	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1383C>T	p.Ser461Ser	synonymous	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.1383C>T	p.Ser461Ser	synonymous	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1383C>T	p.Ser461Ser	synonymous	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1383C>T	p.Ser461Ser	synonymous	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1917 AN: 152020 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00302 AC: 549 AN: 182088 AF XY: 0.00234

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000765

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.00131 AC: 1856 AN: 1416600 Hom.: 35 Cov.: 82 AF XY: 0.00116 AC XY: 811 AN XY: 700938

African (AFR) AF: 0.0441 AC: 1449 AN: 32848

American (AMR) AF: 0.00246 AC: 91 AN: 37052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 38004

South Asian (SAS) AF: 0.000121 AC: 10 AN: 82552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44772

Middle Eastern (MID) AF: 0.00143 AC: 8 AN: 5612

European-Non Finnish (NFE) AF: 0.0000724 AC: 79 AN: 1091368

Other (OTH) AF: 0.00371 AC: 219 AN: 58956

GnomAD4 genome AF: 0.0126 AC: 1921 AN: 152138 Hom.: 47 Cov.: 33 AF XY: 0.0126 AC XY: 937 AN XY: 74366

African (AFR) AF: 0.0438 AC: 1821 AN: 41542

American (AMR) AF: 0.00457 AC: 70 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67996

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00492 Hom.: 1

Bravo AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Oligodontia-cancer predisposition syndrome (5)
-	-	3	not provided (3)
-	-	1	Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.1
DANN	Benign	0.91
PhyloP100		0.77
Mutation Taster		=100/0	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: rs9914661; hg19: chr17-63533771; COSMIC: COSV104596746;