RAD21 c.815-5del, p.?
NM_006265.2:c.815-5del
Likely Benign
The variant NM_006265.2:c.815-5delT in RAD21 is classified as Likely Benign based on stand-alone BA1 due to high population frequency, with additional supporting evidence from computational data (BP4) and reputable benign reports in ClinVar (BP6).
ACMG/AMP Criteria Applied
BA1
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
RAD21
Transcript
NM_006265.3
MANE Select
Total Exons
14
Strand
Reverse (−)
Reference Sequence
NC_000008.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006265.2 | RefSeq Select | 14 exons | Reverse |
| NM_006265.1 | Alternative | 14 exons | Reverse |
Variant Details
HGVS Notation
NM_006265.2:c.815-5del
Protein Change
?
Location
Exon 7
(Exon 7 of 14)
5'Exon Structure (14 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_006265.3
Genome Browser
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HGVS InputNM_006265:c.815-5del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
3.96%
Common
Highest in Population
European (Finnish)
9.48%
Common
Global: 3.96%
European (Finnish): 9.48%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 34906Alt: 1383Homozygotes: 1
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 3.96%, 1383/34906 alleles, homozygotes = 1) and at a higher frequency in the European (Finnish) population (MAF= 9.48%, 294/3100 alleles, homozygotes = 1). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Likely Benign
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
3 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (3 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.13
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is an intronic deletion (c.815-5delT) outside of the canonical ±1 or 2 splice sites and not predicted to cause a null effect. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the definition of a loss-of-function null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: the protein change is unknown and there is no reported amino acid change matching a known pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because there is no matching pathogenic amino acid substitution.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo status or parental testing information is available. Therefore, this criterion is not applied at Not Applied strength because there is no de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assessed.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or affected individual data are available. Therefore, this criterion is not applied at Not Applied strength because prevalence data are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: it is an intronic deletion not in a known functional domain or mutational hotspot. Therefore, this criterion is not applied at Not Applied strength because the location is not a recognized hotspot or domain.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is present in gnomAD at 3.96% overall frequency and 9.48% in European (Finnish) individuals. Therefore, this criterion is not applied at Not Applied strength because the variant is not absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no information on trans configuration with pathogenic alleles is available. Therefore, this criterion is not applied at Not Applied strength because no in trans data exist.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is an intronic deletion without known effect on protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length change.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied at Not Applied strength because it does not involve an amino acid change.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption or family testing data. Therefore, this criterion is not applied at Not Applied strength because de novo status is not assumed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength because familial co-segregation has not been assessed.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet PP2.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico tools (CADD score 0.13, SpliceAI = 0) predict no deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence indicates neutrality.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history information is provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unknown.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: reputable sources report it as benign, not pathogenic. Therefore, this criterion is not applied at Not Applied strength because no pathogenic assertions exist.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: a population frequency of 3.96% overall (gnomAD) and 9.48% in European (Finnish) individuals, exceeding thresholds for a dominant disorder. Therefore, this criterion is applied at Stand Alone strength because the allele frequency is incompatible with disease causation.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: a high population frequency, but BA1 (stand‐alone) has already been applied. Therefore, BS1 is not applied at Not Applied strength because BA1 suffices to establish benign impact.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: presence in gnomAD including homozygotes, but BA1 stand-alone criterion already classifies the variant as benign. Therefore, BS2 is not applied at Not Applied strength because BA1 alone is sufficient.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation has not been assessed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet BP1.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no information on compound genotypes. Therefore, this criterion is not applied at Not Applied strength because cis/trans configuration is unknown.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is an intronic deletion, not an in-frame coding indel. Therefore, this criterion is not applied at Not Applied strength because the variant context does not meet BP3.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: SpliceAI predicts no splice impact (score 0), CADD score 0.13, and other in silico tools indicate benign. Therefore, this criterion is applied at Supporting strength because computational analyses uniformly predict no functional effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with alternate explanations. Therefore, this criterion is not applied at Not Applied strength because no alternative molecular basis is documented.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar entries from three laboratories classifying it as Likely benign and three as Benign. Therefore, this criterion is applied at Supporting strength because reputable databases report a benign classification without underlying data available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is an intronic deletion, not a synonymous coding variant. Therefore, this criterion is not applied at Not Applied strength because BP7 pertains only to synonymous variants.