Variant classification summary

NM_004343.3:c.1066C>G

CALR · NP_004334.1:p.(Gln356Glu) · NM_004343.3

GRCh37: chr19:13054539 C>G · GRCh38: chr19:12943725 C>G

Gene: CALR Transcript: NM_004343.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CALR

Transcript

NM_004343.3

Protein

NP_004334.1:p.(Gln356Glu)

gnomAD AF

9.295569359820336e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 total AF 9.30e-06 (maximum 0.0154%), below the 0.1% rare-variant threshold.

2

BP4 (Supporting): REVEL 0.095, below the 0.290 benign-supporting threshold, with no predicted splice impact (SpliceAI 0.065).

3

Final: VUS, because one supporting pathogenic and one supporting benign criterion satisfy no ACMG/AMP 2015 combination rule.

Final determination: Under generic ACMG/AMP 2015 fallback rules, 1 PM (supporting) + 1 BP (supporting) does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the variant is classified as Uncertain Significance.

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: missense substitution, not a null variant expected to trigger nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no other nucleotide change producing p.Gln356Glu is established as pathogenic.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband phenotype or de novo/parental-testing data were available.
PS3	Not assessed	Not assessed: no functional assay evidence for p.Gln356Glu was available.
PS4	Not assessed	Not assessed: no case-series or case-control prevalence data for this variant were available.
PM1	Not met	Not met: residue 356 lies in the C-terminal acidic tail, outside the exon 9 frameshift hotspot.	oncokb
PM2	Met	Met (supporting): gnomAD v4.1 total AF 9.30e-06 (max 0.0154%), below the 0.1% PM2 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic variant, biallelic genotype, or phase data were available.
PM4	N/A	Not applicable: missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no alternate missense change at codon 356 with an established pathogenic classification.	pm5_candidates
PM6	Not assessed	Not assessed: no evidence of de novo occurrence was available.
PP1	Not assessed	Not assessed: no segregation or pedigree data were available.
PP2	Not met	Not met: CALR disease mechanism is exon 9 frameshift indels, not missense substitution.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.095 is far below the 0.644 pathogenic-supporting threshold, and SpliceAI predicts no splice impact (0.065).	spliceai revel
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnosis data were available.
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic assertion exists for this variant.	clinvar
BA1	Not met	Not met: highest observed population frequency 0.0154% is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 group max FAF 9.20e-05, below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: zero homozygotes observed, which does not meet the BS2 benign-frequency expectation.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay evidence of a benign effect was available.
BS4	Not assessed	Not assessed: no unaffected-relative data were available to evaluate non-segregation.
BP1	Not assessed	Not assessed: CALR's gain-of-function frameshift mechanism does not fit BP1's truncating-disease premise.
BP2	Not assessed	Not assessed: no data on a second pathogenic variant or allele phase were available.
BP3	N/A	Not applicable: missense substitution, not an in-frame indel within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.095 is below the 0.290 benign-supporting threshold, with no predicted splice impact.	revel spliceai
BP5	Not assessed	Not assessed: no alternate-gene explanation for the phenotype was available.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion exists for this variant.	clinvar
BP7	N/A	Not applicable: applies to synonymous variants; this is a missense substitution.	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.