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PKD1c.9850T>CUncertain significance
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Variant interpretation report

PKD1 c.9850T>C, p.(Cys3284Arg)

NM_001009944.3:c.9850T>C NP_001009944.3:p.(Cys3284Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PKD1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen PKD1 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate

This variant is absent from large population databases. In gnomAD v4.1, it is absent in 1,562,318 alleles (0 homozygotes, AF = 0%), absent in gnomAD v2.1, and absent in gnomAD-Canada v1.0. Using generic ACMG/AMP thresholds (PM2: AF < 0.1% with confirmed absence), this meets moderate evidence for pathogenicity.

PP3Supporting
PP3 · supporting

REVEL, a meta-predictor integrating multiple computational methods, scores this variant at 0.754, which exceeds the commonly used pathogenic threshold of 0.5 and supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score (0.242) falls in the uncertain range and does not independently support pathogenicity. REVEL alone provides sufficient computational support for PP3 at the supporting level.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely pathogenic.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PKD1 VCEP v1.0.0, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 6 not met · 15 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

REVEL meta-predictor score of 0.754 supports a deleterious effect, meeting PP3 at supporting strength.

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.

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.

Met · 2

PM2 ModerateThis variant is absent from large population databases. In gnomAD v4.1, it is absent in 1,562,318 alleles (0 homozygotes, AF = 0%), absent in gnomAD v2.1, and absent in gnomAD-Canada v1.0. Using generic ACMG/AMP thresholds (PM2: AF < 0.1% with confirmed absence), this meets moderate evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0/1
  • 562
  • 318 alleles
  • AF = 0.00000%
  • gnomAD v2.1: absent
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL, a meta-predictor integrating multiple computational methods, scores this variant at 0.754, which exceeds the commonly used pathogenic threshold of 0.5 and supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score (0.242) falls in the uncertain range and does not independently support pathogenicity. REVEL alone provides sufficient computational support for PP3 at the supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.754 (deleterious
  • above 0.5 threshold)
  • SpliceAI: max delta = 0.00 (no splicing impact)
  • BayesDel: 0.242 (uncertain range)
Still missing
  • No additional computational predictors (CADD
  • PolyPhen-2
  • SIFT) available.
Sources
revelbayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PP5 Same as PS5: a single ClinVar submission classifies this variant as Likely pathogenic without assertion criteria, which does not meet the PP5 threshold for a reputable source report. Details ▾Hide ▴
Evidence considered
  • Single ClinVar submission (Likely pathogenic
  • no assertion criteria
  • trust tier: weak).
Still missing
  • No expert panel or multi-submitter consensus.
Sources
clinvar ↗
BA1 Global minor allele frequency is 0.0% in gnomAD v4.1, far below the 1% threshold for BA1. The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.0%
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Global minor allele frequency is 0.0%, far below the 0.3% threshold for BS1 in a dominant disorder. The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.0%
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 REVEL score of 0.754 predicts a deleterious effect, contradicting the requirement for multiple lines of computational evidence suggesting no impact on gene product. SpliceAI (max delta 0.0) shows no splicing effect, but REVEL alone precludes BP4 application. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.754 (deleterious
  • contradicts BP4)
  • SpliceAI: max delta = 0.00 (no splicing impact)
  • BayesDel: 0.242 (uncertain)
Sources
revelbayesdelspliceai ↗
BP6 ClinVar classifies this variant as Likely pathogenic (1 submitter), not benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Likely pathogenic
  • not benign.
Sources
clinvar ↗
PS5 ClinVar lists one clinical laboratory submission classifying this variant as Likely pathogenic (SCV004239210), but the submission provides no assertion criteria and has a trust tier of 'weak.' A single submission without documented evidence does not meet the PS5 threshold for a reputable source reporting the variant as pathogenic with unavailable primary evidence. Details ▾Hide ▴
Evidence considered
  • Single ClinVar submission (Likely pathogenic
  • no assertion criteria provided
  • trust tier: weak).
Still missing
  • No expert panel classification
  • no submission with assertion criteria.
Sources
clinvar ↗

Not assessed · 15 · no assessment recorded

PS1 No evidence of a different nucleotide change at codon 3284 with an established pathogenic classification was identified. PS1 requires a previously classified pathogenic variant causing the same amino acid change. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic comparators identified for codon 3284.
Still missing
  • No ClinVar or literature data for other variants at codon 3284.
PS2 No de novo occurrence data with confirmed maternity and paternity were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo reports in ClinVar or literature for this variant.
PS3 No well-established in vitro or in vivo functional studies were identified for NM_001009944.3:c.9850T>C (p.Cys3284Arg). Details ▾Hide ▴
Evidence considered
  • No functional data identified for this specific variant.
Still missing
  • No functional characterization of p.Cys3284Arg in the literature.
PS4 Insufficient data to assess variant prevalence in affected individuals vs controls. A single ClinVar submission classifies this variant as Likely pathogenic (SCV004239210, Molecular Genetics, Labor Dr. Heidrich & Kollegen MVZ GmbH) but provides no assertion criteria and no case-level detail. Details ▾Hide ▴
Evidence considered
  • Single ClinVar submission without assertion criteria
  • no case-control comparison available.
Still missing
  • No case-control or cohort studies reporting this variant.
Sources
clinvar ↗
PM1 The variant does not lie in a statistically significant mutational hotspot per the Cancer Hotspots database. No domain-level functional data are available to assess whether codon 3284 resides in a critical, well-established functional domain of polycystin-1. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot
  • no domain annotation available.
Still missing
  • No domain-level functional annotation for C3284 in polycystin-1.
PM5 No pathogenic missense comparators at codon 3284 were identified through automated ClinVar harvesting. PM5 requires a different pathogenic missense variant at the same amino acid residue. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparators found (pm5_mode: unknown
  • 0 candidates).
Still missing
  • No ClinVar or literature data for other variants at codon 3284.
PM6 No de novo occurrence data (without confirmation of paternity and maternity) were identified for this variant. PM6 requires at least an assumed de novo observation. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo reports for this variant.
PP1 No co-segregation data with disease in multiple affected family members were identified. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies reporting segregation of this variant.
PP2 PKD1 is known to harbor pathogenic missense variants in ADPKD, but gene-level missense constraint data (e.g., missense Z-score, HCI prior) were not available to formally assess a low rate of benign missense variation. HCI prior lookup returned no result. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for this variant
  • no missense constraint data available.
Still missing
  • Gene-level missense constraint metrics not available for PKD1.
PP4 No patient-specific phenotypic data or family history information were available to assess whether the phenotype is highly specific for ADPKD with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • No clinical phenotype or family history data for individuals carrying this variant.
BS2 No data on observation of this variant in healthy adult individuals in the absence of ADPKD. While gnomAD absence is consistent with rarity, it does not directly provide the healthy adult observation required for BS2. Details ▾Hide ▴
Evidence considered
  • No documented observation in healthy adults without ADPKD.
Still missing
  • No phenotype data for individuals in population databases.
BS3 No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No functional data for this variant.
Still missing
  • No functional characterization of p.Cys3284Arg.
BS4 No segregation data demonstrating lack of co-segregation with disease were available. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies for this variant.
BP2 No observation of this variant in trans with a known pathogenic dominant PKD1 variant was identified. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data available.
Still missing
  • No data on co-occurrence with other PKD1 pathogenic variants.
BP5 No case was identified where this variant was found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No co-occurrence data with other disease-causing variants.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001009944.3:c.9850T>C is a missense variant (p.Cys3284Arg). It does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) required for PVS1 application under the generic ClinGen SVI PVS1 framework (PMC6185798). The PKD1 CSPEC VCEP framework (v1.0.0) is in preparation and contains no PVS1 override rules. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant type eligible for PVS1.
Sources
pvs1_generic_framework ↗
PM3 N/ASkipped: PM3 applies to recessive disorders (variants in trans); PKD1-associated ADPKD is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped: PM4 applies to protein length-altering variants (indels, stop-loss); this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/APKD1-associated ADPKD is caused by both missense and truncating variants; the gene is not limited to a primarily truncating disease mechanism. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • PKD1 has many reported pathogenic missense variants in ADPKD.
BP3 N/ASkipped: BP3 applies to in-frame indels in repetitive regions; this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.9850T>C, p.Cys3284Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous variants only.

Identifiers

Gene
PKD1
Transcript
NM_001009944.3
Coding (HGVS c.)
NM_001009944.3:c.9850T>C
Protein (HGVS p.)
NP_001009944.3:p.(Cys3284Arg)
GRCh38
chr16:2099934 A>G
GRCh37
chr16:2149935 A>G
ClinVar
2690992

Gene diagram

Every interpreted variant in PKD1, mapped onto the exon structure of NM_001009944.3. Select a row to find it on the plot.

PKD1NM_001009944.3
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 1,562,318 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,562,318 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +31 bp
0.000
SpliceAI acceptor gainat +128 bp
0.000
SpliceAI donor lossat -40 bp
0.000
SpliceAI donor gainat +245 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.754
BayesDel
0.242

How the predictions were used

PP3 SupportingREVEL, a meta-predictor integrating multiple computational methods, scores this variant at 0.754, which exceeds the commonly used pathogenic threshold of 0.5 and supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score (0.242) falls in the uncertain range and does not independently support pathogenicity. REVEL alone provides sufficient computational support for PP3 at the supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.754 (deleterious
  • above 0.5 threshold)
  • SpliceAI: max delta = 0.00 (no splicing impact)
  • BayesDel: 0.242 (uncertain range)
Still missing
  • No additional computational predictors (CADD
  • PolyPhen-2
  • SIFT) available.
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.754 predicts a deleterious effect, contradicting the requirement for multiple lines of computational evidence suggesting no impact on gene product. SpliceAI (max delta 0.0) shows no splicing effect, but REVEL alone precludes BP4 application. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.754 (deleterious
  • contradicts BP4)
  • SpliceAI: max delta = 0.00 (no splicing impact)
  • BayesDel: 0.242 (uncertain)
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.9850T>C, p.Cys3284Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.754. BayesDel score = 0.242292.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,562,318 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.