rs1555911640
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_007194.4(CHEK2):c.1544del(p.Pro515LeufsTer51) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P515P) has been classified as Likely benign.
Frequency
Consequence
NM_007194.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1544del | p.Pro515LeufsTer51 | frameshift_variant, splice_region_variant | 15/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1544del | p.Pro515LeufsTer51 | frameshift_variant, splice_region_variant | 15/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 02, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 530085). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the CHEK2 gene (p.Pro515Leufs*51). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CHEK2 protein and extend the protein by 21 additional amino acid residues. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at