rs74006838

Variant names:

• chr17-65536509-G-A
• rs74006838
• NM_004655.4:c.1952C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65536509-G-A
• chr17-65536509-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004655.4(AXIN2):​c.1952C>T​(p.Ser651Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,842 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S651W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.889
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041804314).
• BP6: Variant 17-65536509-G-A is Benign according to our data. Variant chr17-65536509-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 127938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (180/152352) while in subpopulation AFR AF = 0.00418 (174/41586). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 180 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.1952C>T	p.Ser651Leu	missense	Exon 8 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1757C>T	p.Ser586Leu	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.1952C>T	p.Ser651Leu	missense	Exon 8 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1757C>T	p.Ser586Leu	missense	Exon 6 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1952C>T	p.Ser651Leu	missense	Exon 8 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000269 AC: 66 AN: 245260 AF XY: 0.000233

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000738

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461490 Hom.: 0 Cov.: 33 AF XY: 0.000103 AC XY: 75 AN XY: 727026

African (AFR) AF: 0.00343 AC: 115 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111984

Other (OTH) AF: 0.000166 AC: 10 AN: 60378

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74500

African (AFR) AF: 0.00418 AC: 174 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0191 Hom.: 2354

Bravo AF: 0.00144

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	AXIN2-related disorder (1)
-	-	1	Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome (1)
-	-	1	not specified (1)
-	-	1	Oligodontia-cancer predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.082
DANN	Benign	0.88
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.89
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.079
Sift	Benign	0.37	T
Sift4G	Benign	0.31	T
Polyphen		0.0080	B
Vest4		0.25
MVP		0.11
MPC		0.16
ClinPred		0.0031	T
GERP RS		-10
gMVP		0.14
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74006838; hg19: chr17-63532627; COSMIC: COSV61060172;