chr17-65534007-GA-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_004655.4(AXIN2):βc.2309delβ(p.Phe770SerfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. F770F) has been classified as Likely benign.
Frequency
Consequence
NM_004655.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.2309del | p.Phe770SerfsTer12 | frameshift_variant | 10/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2309del | p.Phe770SerfsTer12 | frameshift_variant | 10/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.2114del | p.Phe705SerfsTer12 | frameshift_variant | 8/9 | 1 | |||
AXIN2 | ENST00000618960.4 | c.2114del | p.Phe705SerfsTer12 | frameshift_variant | 9/10 | 5 | |||
AXIN2 | ENST00000578251.1 | n.531del | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251496Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 533178). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe770Serfs*12) in the AXIN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AXIN2 are known to be pathogenic (PMID: 15042511, 21416598). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2023 | The c.2309delT variant, located in coding exon 9 of the AXIN2 gene, results from a deletion of one nucleotide at nucleotide position 2309, causing a translational frameshift with a predicted alternate stop codon (p.F770Sfs*12). Based on internal structural assessment, this alteration eliminates most of the DIX domain, which is critical for formation of the Wnt signaling complex (Fiedler M et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Feb;108(5):1937-42). This alteration is expected to result in loss of function by premature protein truncation. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with AXIN2-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at