NM_004655.4:c.2141+73G>A

Variant names:

• chr17-65536247-C-T
• rs4072245
• NM_004655.4:c.2141+73G>A

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.2141+73G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,452,374 control chromosomes in the GnomAD database, including 3,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (287 hom., cov: 33)
  • Exomes 𝑓: 0.063 (2900 hom.)
• Consequence: AXIN2 NM_004655.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00700
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-65536247-C-T is Benign according to our data. Variant chr17-65536247-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.2141+73G>A		intron_variant	Intron 8 of 10	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.2141+73G>A		intron_variant	Intron 8 of 10	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1946+73G>A		intron_variant	Intron 6 of 8	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1946+73G>A		intron_variant	Intron 7 of 9	5		ENSP00000478916.1
AXIN2	ENST00000578251.1	n.363+73G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8287 AN: 152190 Hom.: 289 Cov.: 33

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0860

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0618

Gnomad OTH AF: 0.0599

GnomAD4 exome AF: 0.0635 AC: 82512 AN: 1300066 Hom.: 2900 AF XY: 0.0656 AC XY: 42360 AN XY: 646218

African (AFR) AF: 0.0222 AC: 658 AN: 29704

American (AMR) AF: 0.0303 AC: 1080 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1336 AN: 24516

East Asian (EAS) AF: 0.0767 AC: 2732 AN: 35634

South Asian (SAS) AF: 0.120 AC: 9305 AN: 77238

European-Finnish (FIN) AF: 0.0971 AC: 4724 AN: 48648

Middle Eastern (MID) AF: 0.0894 AC: 351 AN: 3926

European-Non Finnish (NFE) AF: 0.0592 AC: 58590 AN: 990174

Other (OTH) AF: 0.0684 AC: 3736 AN: 54626

GnomAD4 genome AF: 0.0544 AC: 8282 AN: 152308 Hom.: 287 Cov.: 33 AF XY: 0.0574 AC XY: 4273 AN XY: 74466

African (AFR) AF: 0.0255 AC: 1061 AN: 41576

American (AMR) AF: 0.0395 AC: 605 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3470

East Asian (EAS) AF: 0.0854 AC: 443 AN: 5186

South Asian (SAS) AF: 0.116 AC: 559 AN: 4822

European-Finnish (FIN) AF: 0.102 AC: 1085 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0617 AC: 4200 AN: 68026

Other (OTH) AF: 0.0588 AC: 124 AN: 2108

Alfa AF: 0.0578 Hom.: 467

Bravo AF: 0.0479

Asia WGS AF: 0.100 AC: 346 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.1
DANN	Benign	0.79
PhyloP100		-0.0070
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs4072245; hg19: chr17-63532365; COSMIC: COSV104596685;