NM_001009944.3:c.9850T>C (p.Cys3284Arg) is a missense variant in PKD1, associated with autosomal dominant polycystic kidney disease (ADPKD). This variant is absent from gnomAD v4.1 (0/1,562,318 alleles), gnomAD v2.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength.1 REVEL meta-predictor score of 0.754 supports a deleterious effect, meeting PP3 at supporting strength.2 ClinVar contains a single submission (SCV004239210, Labor Dr. Heidrich & Kollegen MVZ GmbH) classifying this variant as Likely pathogenic, but with no assertion criteria provided; this is insufficient to meet PS5 or PP5.3 With only PM2 (moderate) and PP3 (supporting) met, the variant does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 combination rules (PMID:25741868). PM2 + PP3 alone constitutes a Variant of Uncertain Significance. No benign criteria are met.4
PKD1
Final classification
VUS
PKD1 c.9850T>C · p.Cys3284Arg
PKD1
NM_001009944.3:c.9850T>C (p.Cys3284Arg) is a missense variant in PKD1, associated with autosomal dominant polycystic kidney disease (ADPKD).
ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD1 Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, PP3 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
PKD1 c.9850T>C
PM2 + PP3
→
VUS
Gene diagram
· NM_001009944.3 · variants mapped to exon structure
PKD1
NM_001009944.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1562318 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73802 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,562,318
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2690992)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.754. BayesDel score = 0.242292.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links