Classification rationale

BS1BS2 Likely Benign

DICER1 c.4206+11_4206+13del unknown · exon 22i

BS1 (Strong): gnomAD v4.1 East Asian allele frequency 0.00261 (76/29,110 alleles) exceeds the >0.0003 threshold. BS2 (Supporting): gnomAD v4.1 reports 2 homozygotes overall, meeting the VCEP rule for homozygous observations without clinical information. Final classification: Likely Benign, from -5 points (BS1 Strong -4, BS2 Supporting -1) within the -6 to -2 range of the DICER1 VCEP point-based framework.

BS1 + BS2 → Likely Benign

Gene diagram · NM_177438.3 · variants mapped to exon structure

DICER1 NM_177438.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

Met (Strong): gnomAD v4.1 East Asian frequency 0.00261 (76/29,110 alleles) exceeds the >0.0003 BS1 threshold with adequate sample size.

The DICER1 VCEP v1.4 BS1 rule requires frequency >0.0003 (0.03%) in a gnomAD subpopulation, with >2,000 alleles tested and at least 5 alleles present.gnomAD v4.1 reports East Asian frequency 0.0026107867 from 76/29,110 alleles, clearly exceeding the BS1 threshold with adequate allele count and tested-allele count.The gnomAD v4.1 result is the most recent and comprehensive population dataset provided, as directed by the VCEP specification.

cspec ↗gnomad_v4 ↗

BS2 supporting Benign

Met (Supporting): gnomAD v4.1 reports 2 homozygotes overall, meeting the VCEP rule for homozygous observations lacking clinical information.

The DICER1 VCEP v1.4 BS2 Supporting rule permits 2 or more observations of homozygosity in individuals lacking clinical information.gnomAD v4.1 reports 2 homozygotes for the variant overall; the AMR and NFE subpopulations each report one homozygote.gnomAD v2.1 reports 6 homozygotes overall, providing additional population-database observations, but does not provide individual clinical status or parental confirmation.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Assessed · not applied · 4 not met · 12 not assessed

Pathogenic

PVS1 Not met: this deep intronic deletion has no predicted splice impact (SpliceAI max delta 0.012), so no loss-of-function consequence is established.

PS1 Not assessed: no ClinGen DICER1 VCEP pathogenic comparator at this nucleotide was available.

PS2 Not assessed: no parental testing, de novo assertion, or de novo point data were available.

PS3 Not assessed: no validated functional study, RNA assay, or cleavage-assay data were available for this variant.

PS4 Not assessed: no affected probands, phenotype points, or case-control data for this exact variant were available.

PM2 Not met: gnomAD v4.1 total AF 0.000439 (620/1,412,262 alleles) far exceeds the <0.000005 Supporting threshold.

PM4 Not met: this intronic 3-bp deletion has no assigned protein consequence, so no in-frame indel or RNase IIIb residue can be evaluated.

PP1 Not assessed: no affected or genotype-positive relatives, pedigree, or meiosis count were available.

PP3 Not assessed: SpliceAI max delta 0.012 does not support a splice effect, and no MaxEntScan result was available.

PP4 Not assessed: no tumor testing, germline-retention result, or somatic second-hit data were available.

Benign

BA1 Not met: the highest qualifying gnomAD v4.1 subpopulation frequency is 0.00261 in East Asians (76/29,110), below the >0.003 BA1 threshold.

BS3 Not assessed: no benign functional study, RNA evidence, or cleavage assay was available.

BS4 Not assessed: no phenotype-positive, genotype-negative relatives or segregation results were available.

BP2 Not assessed: no trans/cis observations with a pathogenic DICER1 variant, phase data, or parental testing were available.

BP4 Not assessed: although SpliceAI predicts no splice impact (max delta 0.012), the required MaxEntScan concordance result is unavailable.

BP7 Not assessed: BP7 requires BP4, which cannot be assessed without the required MaxEntScan result.

N/A · 10 PM1 · PM3 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000439012; MAF= 0.04390%, 620/1412262 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00261079; MAF= 0.26108%, 76/29110 alleles, homozygotes = 0); grpmax FAF= 0.00213789.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000167591; MAF= 0.01676%, 40/238676 alleles, homozygotes = 6) and has highest observed frequency in the East Asian population (AF= 0.000565163; MAF= 0.05652%, 10/17694 alleles, homozygotes = 2); grpmax FAF= 0.00028983.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.044% · 620 / 1,412,262
2 hom · FAF 0.21%

East Asian 76 / 29,110	0.26%
Admixed American 34 / 48,548	0.07% 1 hom
European (non-Finnish) 456 / 1,060,752	0.043% 1 hom
Middle Eastern 2 / 5,136	0.039%
Remaining individuals 19 / 54,416	0.035%
South Asian 20 / 74,708	0.027%
African/African American 11 / 61,570	0.018%
European (Finnish) 2 / 51,180	0.0039%

+ 2 not observed (Amish, Ashkenazi Jewish)

gnomAD v2.1

0.017% · 40 / 238,676
6 hom · FAF 0.029%

East Asian 10 / 17,694	0.057% 2 hom
European (non-Finnish) 19 / 110,416	0.017% 2 hom
South Asian 4 / 26,516	0.015% 1 hom
African/African American 3 / 20,578	0.015%
Admixed American 3 / 30,064	0.01% 1 hom
European (Finnish) 1 / 18,036	0.0055%

+ 2 not observed (Ashkenazi Jewish, Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 1050748)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 1 PMID not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR