DICER1 c.4206+7_4206+8dup, p.?
NM_177438.3:c.4206+7_4206+8dup
COSMIC ID: COSM8620105
Likely Benign
This intronic DICER1 variant has a high population frequency exceeding VCEP BA1 threshold, multiple homozygous observations (BS2), and concordant computational predictions indicating no splicing impact (BP4, BP7), supported by a benign ClinVar classification (BP6). Stand-alone BA1 suffices for a Benign classification.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
DICER1
Transcript
NM_177438.3
MANE Select
Total Exons
27
Strand
Reverse (−)
Reference Sequence
NC_000014.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_177438.2 | RefSeq Select | 27 exons | Reverse |
| NM_177438.1 | Alternative | 27 exons | Reverse |
Variant Details
HGVS Notation
NM_177438.3:c.4206+7_4206+8dup
Protein Change
?
Location
Exon 22
(Exon 22 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM8620105
Variant interpretation based on transcript NM_177438.3
Genome Browser
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HGVS InputNM_177438:c.4206+7_4206+8dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.945%
Common
Highest in Population
African/African American
2.94%
Common
Global: 0.945%
African/African American: 2.94%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 200280Alt: 1892Homozygotes: 578
ACMG Criteria Applied
BS1
This variant is present in gnomAD (MAF= 0.945%, 1892/200280 alleles, homozygotes = 578) and at a higher frequency in the African/African American population (MAF= 2.94%, 582/19794 alleles, homozygotes = 128). The variant frequency (0.3% <= MAF <= 1%) supports BS1 criterion application.
Classification
1 publications
Benign
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
6 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
ACMG criteria met: None
Clinical Statement
This variant has been reported in ClinVar as Benign (6 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The DICER1 4206+7_4206+8dup variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with exceptions..." The evidence for this variant shows it is located at positions +7 and +8, outside the canonical splice donor/acceptor sites. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the requirement for canonical splice site disruption.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Strong Strength: same amino acid change as a known pathogenic variant with no difference in splicing." The evidence for this variant shows it is intronic with no predicted amino acid change. Therefore, this criterion is not applied at Not Applied strength.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "Very Strong Strength: confirmed de novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of de novo occurrence provided. Therefore, this criterion is not applied at Not Applied strength.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong: RNA assay shows splicing impact that is out-of-frame..." There are no functional RNA splicing assay data for this variant. Therefore, this criterion is not applied at Not Applied strength due to lack of functional evidence.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Strong Strength: statistical evidence from case-control data or phenotype points ≥4." No case-control or phenotype point data are available. Therefore, this criterion is not applied at Not Applied strength.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: putative missense variants at metal ion-binding residues in RNase IIIb domain." This variant is intronic and not a missense change in the RNase IIIb domain. Therefore, this criterion is not applied at Not Applied strength.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: allele frequency <0.000005 across gnomAD." The evidence for this variant shows a global MAF of approximately 0.00945 (0.945%) and up to 2.94% in African/African American populations, which exceeds the threshold. Therefore, this criterion is not applied at Not Applied strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate Strength: detected in trans with a pathogenic variant in a recessive disorder." DICER1 disease mechanism is dominant, and no trans observations are reported. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: in-frame indels within RNase IIIb domain; Supporting Strength: in-frame indels outside RNase IIIb domain." This variant is an intronic duplication, not an in-frame indel in coding sequence. Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Moderate Strength: novel missense change at an amino acid residue where a different missense change is pathogenic." This variant is intronic, not a missense change. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Supporting Strength: assumed de novo, but without confirmation of paternity and maternity." No de novo evidence is provided. Therefore, this criterion is not applied at Not Applied strength.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Supporting Strength: cosegregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: missense variant in a gene with low rate of benign missense variation and pathogenic missense variants are common." This is an intronic variant, not missense. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength for splicing variants: concordance of MaxEntScan and SpliceAI predicting splicing effects." SpliceAI score is 0.01, predicting no significant splicing impact, and no MaxEntScan evidence of splice alteration. Therefore, this criterion is not applied at Not Applied strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Strength: somatic tumor testing identifies a second hit in hotspot codon and retention of germline variant." No tumor or somatic data are available. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: reputable source reports variant as pathogenic without available evidence." No such pathogenic assertions exist. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Stand Alone) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: frequency >0.003 (0.3%) in gnomAD subpopulations." The evidence for this variant shows MAF 0.945% overall and 2.94% in African/African American populations, exceeding the threshold. Therefore, this criterion is applied at Stand Alone strength because the allele frequency is above the established benign threshold.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: frequency >0.0003 (0.03%) in gnomAD subpopulations." The evidence for this variant shows MAF 0.945% overall and 2.94% in African/African American populations, exceeding the threshold. Therefore, this criterion is applied at Strong strength because the allele frequency is substantially above the threshold.
BS2
BS2 (Strong)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: 2+ observations of homozygosity in healthy individuals." The evidence for this variant shows 578 homozygotes globally and 128 homozygotes in African/African American populations in gnomAD. Therefore, this criterion is applied at Strong strength because multiple homozygous observations in healthy individuals are documented.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: no splicing impact observed via RNA assay for intronic variants (observed more than once)." No RNA assay data are available for this variant. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Strong Strength: non-segregation in affected family members." No family segregation data are available. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: missense variant in a gene where only loss-of-function causes disease." This is an intronic variant. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: observation in trans with P/LP variant or in cis with multiple P/LP variants." No such observations exist. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: in-frame indel in repetitive region without known function." This is an intronic duplication, not an in-frame coding indel. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: for intronic/non-coding variants, concordance of MaxEntScan and SpliceAI predicting no splicing effects." The evidence for this variant shows SpliceAI score of 0.01 and no MaxEntScan predicted impact. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting Strength: variant found in a case with an alternate molecular basis for disease." No such case data are available. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: reputable source reports variant as benign without available evidence." The evidence for this variant shows ClinVar reports it as benign from 6 laboratories. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: silent or intronic variant at or beyond +7 to -21 positions if BP4 is met." The evidence for this variant shows it is at positions +7/+8 and BP4 is met. Therefore, this criterion is applied at Supporting strength because it meets the intronic position and computational benign criteria.