Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000548.5 | MANE Select | 6415 nt | 111–5534 |
| NM_000548.2 | Alternative | 5543 nt | 19–5442 |
| NM_000548.3 | Alternative | 5675 nt | 107–5530 |
| NM_000548.4 | Alternative | 5751 nt | 201–5624 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as benign (1 clinical laboratories) and as Likely Benign (1 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 289 bp |
| Donor Loss (DL) | 0.0 | 199 bp |
| Acceptor Gain (AG) | 0.01 | 89 bp |
| Donor Gain (DG) | 0.16 | 1 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multi-exon deletion) in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows: NM_000548.5:c.5068+9G>A is an intronic change outside the canonical splice sites and does not introduce a stop codon or frameshift. Therefore, this criterion is not applied as the variant does not meet PVS1 requirements.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: NM_000548.5:c.5068+9G>A does not alter an amino acid residue and no established pathogenic variant at the same residue exists. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no functional assays have been performed for NM_000548.5:c.5068+9G>A. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or affected cohort data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: NM_000548.5:c.5068+9G>A lies outside known functional domains and hot spots. Therefore, PM1 is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: observed at MAF=0.0157% in gnomAD, below thresholds for common variation. Therefore, PM2 is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: TSC2-associated disease is autosomal dominant and no trans observations are reported. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: NM_000548.5:c.5068+9G>A does not affect coding sequence length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: intronic location, not a missense change. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo transmission data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: intronic location, not applicable. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows: in silico algorithms predict no impact on splicing and CADD score suggests benign. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype data provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without accessible evidence'. The evidence for this variant shows: ClinVar submissions include benign and VUS designations, no pathogenic reports. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: MAF=0.0157%, well below BA1 threshold of 5%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF remains extremely low. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: no healthy adult phenotype data. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional assays performed. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. The evidence for this variant shows: intronic change. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: intronic SNV, not an indel. Therefore, BP3 is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. The evidence for this variant shows: SpliceAI predicts no significant splicing impact (max score 0.16) and CADD score -0.46 indicates benign. Therefore, BP4 is applied at Supporting strength because computational tools predict no deleterious effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such case reports. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence'. The evidence for this variant shows: ClinVar assertions are publicly accessible. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: intronic location, not synonymous. Therefore, BP7 is not applied.