Variant classification summary

NM_144997.7:c.1333G>A

FLCN · NP_659434.2:p.(Ala445Thr) · NM_144997.7

GRCh37: chr17:17118598 C>T · GRCh38: chr17:17215284 C>T

Gene: FLCN Transcript: NM_144997.7

Final call

Benign

BA1 stand-alone benign BP1 supporting

Variant details

Gene

FLCN

Transcript

NM_144997.7

Protein

NP_659434.2:p.(Ala445Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The FLCN c.1333G>A (p.Ala445Thr) variant has been reported in ClinVar predominantly as likely benign or benign, with only a single uncertain significance submission.

2

This variant is common in population databases, including gnomAD v2.1 with a total allele frequency of 0.25848% and a highest observed subpopulation frequency of 0.37088%, and gnomAD v4.1 with a total allele frequency of 0.29305% and a Middle Eastern population frequency of 1.35269%, which exceeds the usual benign stand-alone threshold of 1%.

3

FLCN-related disease is primarily associated with loss-of-function variants, and the reviewed FLCN mutation database reported only 2 missense variants among 53 unique germline mutations, which supports a benign interpretation for this missense change.

4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	FLCN loss of function is an established disease mechanism, but this variant is a missense substitution and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site change.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this nucleotide change results in the same amino acid change as a previously established pathogenic variant.
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified for this variant.
PS3	Not assessed	No well-established functional study demonstrating a damaging effect specific to this variant was identified.	PMID:19116017 PMID:19562744
PS4	Not met	This variant has been reported in ClinVar, but no evidence was identified showing statistically increased prevalence in affected individuals compared with controls; its relatively high population frequency also argues against case enrichment.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no evidence was identified placing Ala445 in a well-established critical functional domain without benign variation.	hotspots oncokb
PM2	Not met	Population frequency is above the PM2 rarity threshold of 0.1%: gnomAD v2.1 total AF is 0.25848% and gnomAD v4.1 total AF is 0.29305%, so this variant is not rare enough for PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event.
PM5	Not assessed	No evidence was identified for a different pathogenic missense change at the same amino acid residue that would support PM5.
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified to show that this variant tracks with disease in affected family members.
PP2	Not assessed	Available evidence does not establish that FLCN is a gene in which pathogenic missense variation is a common disease mechanism and benign missense variation is uncommon.	PMID:19562744
PP3	Not assessed	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, and no cited missense-specific calibrated prediction framework was available in the reviewed sources to support PP3.	spliceai
PP4	Not assessed	No phenotype or family history data were provided that would establish a highly specific clinical presentation attributable to a single genetic etiology for this variant.
PP5	N/A	PP5 was not applied because assertion-based evidence from external classifications is not used as stand-alone support when primary evidence is available.	clinvar
BA1	Met	This variant exceeds the benign stand-alone population threshold of 1% in gnomAD v4.1, where the highest observed subpopulation frequency is 1.35269% in the Middle Eastern population (82/6062 alleles).	gnomad_v4
BS1	N/A	This variant exceeds the BS1 threshold of 0.3% in gnomAD, but BA1 already applies because the Middle Eastern population frequency in gnomAD v4.1 is above the 1% benign stand-alone threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	This variant is observed in population databases, including homozygotes, but available evidence is insufficient to determine whether observation in apparently unaffected individuals can be used as a stand-alone BS2 argument for FLCN-associated disease.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating a benign effect specific to this variant was identified.	PMID:19116017 PMID:19562744
BS4	Not assessed	No family data were identified showing lack of segregation with disease.
BP1	Met	FLCN-related disease is primarily associated with loss-of-function variants, and the reviewed FLCN mutation database reported only 2 missense variants among 53 unique germline mutations, making a missense mechanism less likely for this gene.	PMID:19562744 pvs1_gene_context
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region without a known function.
BP4	Not assessed	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, but the reviewed sources did not provide a cited missense-specific calibrated framework sufficient to apply BP4 for protein effect.	spliceai
BP5	Not assessed	No evidence was identified showing that this variant occurs in a case with an alternate molecular basis that fully explains the phenotype.
BP6	N/A	BP6 was not applied because assertion-based evidence from external classifications is not used as stand-alone support when primary evidence is available.	clinvar
BP7	N/A	BP7 does not apply because this variant is missense rather than synonymous or intronic.

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