Variant classification summary

NM_004343.4:c.1154_1155insTTGTC

CALR · NP_004334.1:p.(Lys385AsnfsTer47) · NM_004343.4

GRCh37: chr19:13054627 A>ATTGTC · GRCh38: chr19:12943813 A>ATTGTC

Gene: CALR Transcript: NM_004343.4

Final call

VUS

PM2 supporting

Variant details

Gene

CALR

Transcript

NM_004343.4

Protein

NP_004334.1:p.(Lys385AsnfsTer47)

gnomAD AF

2.651799751235928e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 shows an allele frequency of 2.6518e-05, below the supplied threshold, with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold, so the call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: terminal-exon p.(K385Nfs*47) is predicted to escape NMD, and the exact CALR insertion is associated with an altered oncogenic C terminus rather than established loss of function.	pvs1_variant_assessment PMID:24325356 PMID:24325359 PMID:25741868
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history assessment, or confirmed maternity and paternity is available for this variant.
PS3	Not assessed	Not assessed: exact-variant assays confirmed expression but found no difference in reported localization or cell-surface CALR, without a validated damaging functional readout.	PMID:24325359 PMID:24325356 PMID:25741868
PS4	Not assessed	Not assessed: exact-variant cohort reports lack a control comparison, so the required OR >5.0 and confidence-interval test cannot be calculated.	PMID:24325356 PMID:24325359
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 AF is 2.6518e-05, below the supplied PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no recessive inheritance context or parental/offspring testing establishes this variant in trans with a pathogenic variant.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no affected proband or assumed de novo occurrence is documented, and no parental testing or germline case evidence is available.
PP1	Not assessed	Not assessed: zero affected relatives and zero informative variant-positive meioses are documented for evaluating cosegregation.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this is a frameshift variant, outside the generic PP3 missense or splice-region/intronic scope.
PP4	Not assessed	Not assessed: available reports associate the variant with myeloproliferative neoplasms but provide no case-specific phenotype or single-etiology evidence.	PMID:24325356 PMID:24325359
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic classification; its four Pathogenic submissions are non-expert laboratory assertions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.908e-05, far below the 0.05 BA1 stand-alone threshold.	gnomad_v4 gnomad_v2 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.908e-05, below the generic 0.01 BS1 frequency threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no identified healthy adult individual observation required for BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: negative localization and cell-surface findings did not establish normal protein function or unaffected splicing, and partial endoplasmic-reticulum loss remained possible.	PMID:24325359 PMID:25741868
BS4	Not assessed	Not assessed: no affected family members with documented variant status and phenotype are available to demonstrate lack of segregation.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase-resolved observation demonstrates this variant in trans or cis with a pathogenic variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: this is a frameshift variant, so SpliceAI max delta 0.04 cannot support BP4's no-impact conclusion.
BP5	Not assessed	Not assessed: no exact-variant case is documented with an independent alternate molecular basis for the disease.	PMID:24325359
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.