chr17-65558473-G-A
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004655.4(AXIN2):c.148C>T(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,605,836 control chromosomes in the GnomAD database, including 201,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50F) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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AXIN2 | ENST00000307078.10 | c.148C>T | p.Pro50Ser | missense_variant | Exon 2 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
ENSG00000266076 | ENST00000577662.1 | n.*324C>T | non_coding_transcript_exon_variant | Exon 4 of 7 | 2 | ENSP00000462418.1 | ||||
ENSG00000266076 | ENST00000577662.1 | n.*324C>T | 3_prime_UTR_variant | Exon 4 of 7 | 2 | ENSP00000462418.1 |
Frequencies
GnomAD3 genomes AF: 0.396 AC: 60184AN: 151988Hom.: 14295 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.474 AC: 117123AN: 247006 AF XY: 0.479 show subpopulations
GnomAD4 exome AF: 0.502 AC: 729689AN: 1453730Hom.: 187519 Cov.: 79 AF XY: 0.500 AC XY: 361223AN XY: 721970 show subpopulations
GnomAD4 genome AF: 0.396 AC: 60181AN: 152106Hom.: 14296 Cov.: 32 AF XY: 0.396 AC XY: 29414AN XY: 74352 show subpopulations
ClinVar
Submissions by phenotype
not specified Benign:6
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Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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Oligodontia-cancer predisposition syndrome Benign:5
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not provided Benign:4
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Variant summary: The c.148C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant is found in 56448/119156 control chromosomes (14394 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4737319, which is about 3335 times greater than the maximal expected frequency of a pathogenic allele (0.0001421), suggesting this variant is a very common benign polymorphism. In a case-control study, authors found that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed (Kanzaki_IJMM_2006). Taken together, this variant was classified as Benign. -
This variant is associated with the following publications: (PMID: 26514524, 29114927, 28204848, 27153395, 16820935, 19065536) -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as 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