PRKAR1A c.770-24G>A, p.?
NM_212471.3:c.770-24G>A
COSMIC ID: COSN31925098, COSN31926826
Likely Benign
The variant NM_212471.3:c.770-24G>A in PRKAR1A is common in population databases (MAF 71.8%, numerous homozygotes) and computational/splice predictions show no impact. Multiple strong benign criteria (BA1, BS1, BS2) and supporting benign criteria (BP4, BP6) apply, leading to a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
PRKAR1A
Transcript
NM_212471.3
Total Exons
11
Strand
Forward (+)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_212471.1 | Alternative | 11 exons | Forward |
| NM_212471.2 | Alternative | 11 exons | Forward |
Variant Details
HGVS Notation
NM_212471.3:c.770-24G>A
Protein Change
?
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN31925098, COSN31926826
Variant interpretation based on transcript NM_212471.3
Genome Browser
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HGVS InputNM_212471:c.770-24G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
71.8%
Common
Highest in Population
East Asian
90.0%
Common
Global: 71.8%
East Asian: 90.0%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282600Alt: 202960Homozygotes: 74051
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 71.8%, 202960/282600 alleles, homozygotes = 74051) and at a higher frequency in the East Asian population (MAF= 90.0%, 17947/19948 alleles, homozygotes = 8063). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (3 clinical laboratories).
COSMIC ID
COSN31925098, COSN31926826
Recurrence
139 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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: 0.06
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 change at c.770-24, outside the canonical ±1 or ±2 splice sites. Therefore, PVS1 is not applied because the variant does not meet the definition of a null variant at canonical splice sites.
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 protein change or amino acid substitution. Therefore, PS1 is not applied because there is no amino acid change to compare to known pathogenic variants.
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 data or family history information. Therefore, PS2 is not applied due to lack of de novo confirmation.
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, PS3 is not applied because functional data are missing.
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 cohort data. Therefore, PS4 is not applied due to absence of prevalence data.
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 intronic and not within a known functional domain. Therefore, PM1 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 it has a MAF of 71.8% in gnomAD, far above the threshold for rarity. Therefore, PM2 is not applied because the variant is common in controls.
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 data on trans configuration with pathogenic variants. Therefore, PM3 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 intronic with no effect on protein length. Therefore, PM4 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 missense change. Therefore, PM5 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 or parental relationship data. Therefore, PM6 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 segregation data. Therefore, PP1 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 it is intronic, not missense. Therefore, PP2 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 in silico tools (CADD=0.06, SpliceAI max=0.17) predict no deleterious effect. Therefore, PP3 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 information. Therefore, PP4 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 only benign reports in ClinVar. Therefore, PP5 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 a MAF of 71.8% in gnomAD with 74,051 homozygotes. Therefore, BA1 is applied at Stand Alone strength because the allele frequency far exceeds any credible threshold for pathogenicity.
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 a MAF of 71.8%, which is orders of magnitude higher than expected for a Mendelian disorder. Therefore, BS1 is applied at Strong strength.
BS2
BS2 (Strong)
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 74,051 homozygotes in gnomAD, indicating presence in healthy individuals. Therefore, BS2 is applied at Strong strength.
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 study data. Therefore, BS3 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 no segregation data. Therefore, BS4 is not applied.
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 intronic, not missense. Therefore, BP1 is not applied.
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 phase with other variants. Therefore, BP2 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 change in an intron. Therefore, BP3 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 (e.g., conservation, splicing impact)". The evidence for this variant shows CADD=0.06 and SpliceAI max=0.17, both indicating no impact. Therefore, BP4 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 case reports. Therefore, BP5 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 records from three laboratories classifying it as benign without primary data. Therefore, BP6 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 intronic, not a synonymous coding change. Therefore, BP7 is not applied.