AIP c.682C>A, p.Gln228Lys
NM_003977.4:c.682C>A
COSMIC ID: COSM4146206
Likely Benign
The variant NM_003977.4:c.682C>A (Q228K) is extremely common in population databases (MAF 95%), fulfilling BA1 stand-alone criterion for benign classification. Strong population evidence (BS1), supporting gene mechanism evidence (BP1), computational benign predictions (BP4), and reputable benign source (BP6) further support a classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BP1
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
AIP
Transcript
NM_003977.4
MANE Select
Total Exons
6
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_003977.2 | Alternative | 6 exons | Forward |
| NM_003977.3 | Alternative | 6 exons | Forward |
Variant Details
HGVS Notation
NM_003977.4:c.682C>A
Protein Change
Q228K
Location
Exon 5
(Exon 5 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 228 in gene AIP
Alternate Identifiers
COSM4146206
Variant interpretation based on transcript NM_003977.4
Genome Browser
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HGVS InputNM_003977:c.682C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
95.0%
Common
Highest in Population
Ashkenazi Jewish
100.0%
Common
Global: 95.0%
Ashkenazi Jewish: 100.0%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 279872Alt: 265822Homozygotes: 129214
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 95.0%, 265822/279872 alleles, homozygotes = 129214) and at a higher frequency in the Ashkenazi Jewish population (MAF= 100.0%, 10225/10226 alleles, homozygotes = 5112). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
9 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (9 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
No evidence of other pathogenic variants at position 228 in gene AIP
Functional Summary
The AIP Q228K 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
REVEL Score
0.117
0.117
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.87polyphen_prediction: benignmutationtaster: Pmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
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 a missense change (Q228K), not a null variant. Therefore, this criterion is not applied.
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: no known pathogenic variant at amino acid Q228 with a different nucleotide change. Therefore, this criterion is not applied.
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: parental testing data are not available to confirm de novo occurrence. Therefore, this criterion is not applied.
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.
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 prevalence data. Therefore, this criterion is not applied.
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: Q228 is not in a known mutational hotspot or critical domain. Therefore, this criterion is not applied.
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: MAF is 95.0% in gnomAD, far above an extremely low frequency. Therefore, this criterion is not applied.
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 occurrence with a pathogenic variant. Therefore, this criterion is not applied.
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 a missense change without alteration of protein length. Therefore, this criterion is not applied.
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: no other pathogenic missense change reported at residue Q228. Therefore, this criterion is not applied.
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 status information. Therefore, this criterion is not applied.
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 family segregation data. Therefore, this criterion is not applied.
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: although AIP has pathogenic missense variants, the extremely high population frequency argues against pathogenicity. Therefore, this criterion is not applied.
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: computational tools predict benign effect (REVEL 0.12, CADD, PolyPhen, SpliceAI). Therefore, this criterion is not applied.
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 data provided. Therefore, this criterion is not applied.
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.
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: MAF 95.0% in gnomAD with 129,214 homozygotes, far exceeding any threshold for pathogenicity. Therefore, this criterion is applied at Stand Alone strength.
BS1
BS1 (Strong)
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: MAF 95.0% in population databases, far exceeding disease prevalence. Therefore, this criterion is applied at Strong strength.
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: although many homozygotes exist, clinical phenotype data are not available to confirm health status. Therefore, this criterion is not applied.
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 assays performed. Therefore, this criterion is not applied.
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: segregation data are not available. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
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: AIP disease mechanism is loss of function and Q228K is a missense change. Therefore, this criterion is applied at Supporting strength.
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 data on cis/trans with another variant. Therefore, this criterion is not applied.
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 a single nucleotide missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: REVEL score 0.12 below threshold, benign predictions from CADD, PolyPhen, and minimal SpliceAI impact (max 0.04). Therefore, this criterion is applied at Supporting strength.
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 such case information available. Therefore, this criterion is not applied.
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 reports it as Benign by nine clinical laboratories. Therefore, this criterion is applied at Supporting strength.
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 a missense change, not synonymous. Therefore, this criterion is not applied.