Starting
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PTPN11
Final classification
Benign
PTPN11 c.526-8C>A · p.?
PTPN11

The PTPN11 NM_001330437.1:c.526-8C>A (NP_001317366.1:p.?) variant has been reported in ClinVar and is classified as Benign by the ClinGen RASopathy Variant Curation Expert Panel.

Gene
PTPN11
Transcript
NM_001330437.1
HGVS · transcript:coding
NM_001330437.1:c.526-8C>A
Consequence
N/A
GRCh38
chr12:112454556 C>A
GRCh37
chr12:112892360 C>A
Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting benign; maps to Benign. ▾
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting benign; maps to Benign.
Classification rationale
BA1BS1BP4BP6 Benign
PTPN11 c.526-8C>A

The PTPN11 NM_001330437.1:c.526-8C>A (NP_001317366.1:p.?) variant has been reported in ClinVar and is classified as Benign by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is present in gnomAD v2.1 at 0.06730% and in gnomAD v4.1 at 0.13022%, which are both above the PTPN11 BA1 threshold of 0.05% and the BS1 threshold of 0.025%.2 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, which supports BP4 and does not support PP3 for a splice-region effect.3

BA1 + BS1 + BP4 + BP6 → Benign
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗
3 spliceai ↗cspec ↗
Gene diagram · NM_001330437.1 · variants mapped to exon structure
PTPN11 NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 0.00130217; MAF= 0.13022%, 2078/1595796 alleles, homozygotes = 4) and has highest observed frequency in the European (non-Finnish) population (AF= 0.001701; MAF= 0.17010%, 1980/1164018 alleles, homozygotes = 2); grpmax FAF= 0.00163779.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.000673019; MAF= 0.06730%, 190/282310 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00129804; MAF= 0.12980%, 167/128656 alleles, homozygotes = 0); grpmax FAF= 0.00111834.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.13% · 2078 / 1,595,796
      4 hom · FAF 0.16%
      European (non-Finnish)
      1980 / 1,164,018
      0.17%
      2 hom
      Remaining individuals
      57 / 61,836
      0.092%
      1 hom
      African/African American
      25 / 74,664
      0.033%
      Admixed American
      9 / 59,958
      0.015%
      European (Finnish)
      7 / 64,016
      0.011%
      1 hom
      + 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
      gnomAD v2.1
      0.067% · 190 / 282,310
      1 hom · FAF 0.11%
      European (non-Finnish)
      167 / 128,656
      0.13%
      Remaining individuals
      5 / 7,208
      0.069%
      African/African American
      7 / 24,968
      0.028%
      Admixed American
      8 / 35,434
      0.023%
      European (Finnish)
      3 / 25,122
      0.012%
      1 hom
      + 3 not observed (Ashkenazi Jewish, East Asian, South Asian)
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (12 clinical laboratories) and as Likely benign (9 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 36709)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has previously been reported in somatic cancers (COSMIC; COSV105261528, n = 1 times).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC