rs141699123
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004655.4(AXIN2):c.1900C>T(p.Pro634Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P634L) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1900C>T | p.Pro634Ser | missense_variant | 7/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1900C>T | p.Pro634Ser | missense_variant | 7/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1713-323C>T | intron_variant | 1 | |||||
AXIN2 | ENST00000618960.4 | c.1713-323C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250782Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135674
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460890Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6AN XY: 726752
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the AXIN2 protein (p.Pro634Ser). This variant is present in population databases (rs141699123, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 464579). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AXIN2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
AXIN2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 04, 2023 | The AXIN2 c.1900C>T variant is predicted to result in the amino acid substitution p.Pro634Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-63532994-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at