About PRKD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PRKD1 c.2130A>C, p.(Glu710Asp)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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 Not recorded. 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
PM2Supporting
PM2 · supporting
NM_002742.3:c.2130A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (whole genomes), consistent with a rare variant in large population cohorts.
PP3Supporting
PP3 · supporting
REVEL score of 0.744 exceeds the commonly used threshold of 0.7 for pathogenic prediction, supporting a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score of 0.117 does not independently support pathogenicity, but the REVEL score provides computational evidence of a damaging effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRKD1, a serine/threonine kinase, is mutated in salivary gland carcinomas.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002742.3:c.2130A>C (p.Glu710Asp) is a missense variant in PRKD1, a gene associated with autosomal dominant syndromic congenital heart disease with ectodermal dysplasia (Alter et al. 2021, PMID:32817298).
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level.
REVEL in silico prediction score of 0.744 supports a deleterious effect, meeting PP3 at supporting level. BayesDel score of 0.117 is discordant and does not independently support pathogenicity.
No functional studies, case-control data, segregation data, de novo reports, or ClinVar submissions are available for this variant. The variant has not been reported in any reviewed publication.
The only criteria met are PM2 (supporting) and PP3 (supporting). Under generic ACMG/AMP 2015 classification rules (Richards et al. 2015, PMID:25741868), two supporting criteria are insufficient to reach even Likely Pathogenic classification. This variant falls into the Variant of Uncertain Significance category pending additional evidence.
No criteria match.
Met · 2
PM2 SupportingNM_002742.3:c.2130A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (whole genomes), consistent with a rare variant in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
PP3 SupportingREVEL score of 0.744 exceeds the commonly used threshold of 0.7 for pathogenic prediction, supporting a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score of 0.117 does not independently support pathogenicity, but the REVEL score provides computational evidence of a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.744 (≥0.7 threshold).
- SpliceAI max delta: 0.00 (no splice impact).
- BayesDel score: 0.117.
Still missing
- BayesDel score is discordant with REVEL prediction.
Sources
Not met · 16 · evaluated, threshold not reached
PS4 No case-control studies or enriched prevalence data are available. NM_002742.3:c.2130A>C has not been reported in affected individuals in the literature or ClinVar, precluding any statistical assessment of disease association. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar. No patient reports in any reviewed publication.
Still missing
- No affected individuals reported for this variant.
Sources
PM1 While p.Glu710Asp is located within the PRKD1 protein kinase domain (residues approximately 587-845), no evidence establishes this residue as a mutational hotspot, and domain-specific constraint data demonstrating absence of benign variation in the kinase domain are not available. Cancer Hotspots analysis is negative for this position. Details ▾Hide ▴
Evidence considered
- Position 710 is in the kinase domain but is not a statistically significant hotspot per cancerhotspots.org. No benign variation constraint data available for PRKD1 kinase domain.
Still missing
- Domain-specific missense constraint metrics are unavailable for PRKD1.
PP1 No co-segregation data are available for NM_002742.3:c.2130A>C. No family studies including this variant have been reported. Details ▾Hide ▴
Evidence considered
- No co-segregation data available in any source.
Still missing
- Segregation analysis has not been performed for this variant.
PP2 While missense variants are a recognized disease mechanism for PRKD1 (e.g., p.Gly592Arg and p.Arg603His reported as de novo disease-causing mutations), a low rate of benign missense variation in this gene has not been established. No HCI prior score is available, and no population-level missense constraint metric (e.g., Z-score) supports a depletion of benign missense variants in PRKD1. Details ▾Hide ▴
Evidence considered
- Missense variants are a known mechanism for PRKD1 disease (Alter et al. 2021)
- but no missense constraint data available.
Still missing
- Missense constraint Z-score or HCI prior not available for PRKD1.
Sources
pvs1_gene_context
PP4 No patient phenotype or family history data are available for the individual carrying NM_002742.3:c.2130A>C. The specificity of the phenotype for PRKD1-related disease cannot be assessed. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for this variant.
Still missing
- Patient phenotype information is not available.
PP5 NM_002742.3:c.2130A>C is absent from ClinVar and has not been reported as pathogenic or likely pathogenic by any reputable diagnostic laboratory or clinical source. Details ▾Hide ▴
BA1 NM_002742.3:c.2130A>C is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada). The allele frequency is 0%, far below the >1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0% in all population databases
- does not meet BA1 threshold of >1%.
Sources
BS1 NM_002742.3:c.2130A>C is absent from all population databases. The allele frequency is 0%, far below the >0.3% BS1 threshold for a rare disease variant. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0% in all population databases
- does not meet BS1 threshold of >0.3%.
Sources
BS2 No observations of NM_002742.3:c.2130A>C in healthy adult individuals have been reported. With an allele frequency of 0% in all population databases, there is no evidence that this variant occurs in healthy adults. Details ▾Hide ▴
Evidence considered
- Variant is absent from all population databases
- no healthy adult carriers identified.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing are available for NM_002742.3:c.2130A>C. Details ▾Hide ▴
Evidence considered
- No functional studies available for p.Glu710Asp.
Still missing
- Functional studies are required to assess impact of p.Glu710Asp.
Sources
BS4 No segregation data are available to assess whether NM_002742.3:c.2130A>C fails to co-segregate with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Family segregation analysis has not been performed.
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. PRKD1-associated disease is caused by both missense and truncating variants (e.g., p.Gly592Arg, p.Arg603His are established pathogenic missense variants). Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Both missense and loss-of-function variants are reported as pathogenic in PRKD1 (Alter et al. 2021
- Sifrim et al. 2016).
Sources
pvs1_gene_context
BP2 No data are available regarding observation of NM_002742.3:c.2130A>C in trans with a pathogenic variant for this dominant disorder, or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans/cis configuration data available.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score of 0.744 predicts a deleterious effect rather than no impact. Therefore BP4 does not apply. Details ▾Hide ▴
Evidence considered
- REVEL score 0.744 suggests damaging effect
- inconsistent with BP4 which requires evidence of no impact.
Sources
BP5 No observation of NM_002742.3:c.2130A>C in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Evidence considered
- No cases reported with alternate molecular cause.
BP6 NM_002742.3:c.2130A>C is absent from ClinVar and has not been reported as benign or likely benign by any reputable source. Details ▾Hide ▴
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). NM_002742.3:c.2130A>C is a missense substitution (p.Glu710Asp). Per ClinGen SVI PVS1 framework (PMC6185798), this variant does not fall into any default PVS1 null-variant bucket. Details ▾Hide ▴
Evidence considered
- Missense variant p.Glu710Asp
- apply_generic_pvs1_framework is false per variant-level assessment.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo established pathogenic variant at amino acid residue Glu710 has been identified. PS1 requires a previously characterized pathogenic amino acid change at the same position, which is absent for this residue. Details ▾Hide ▴
Evidence considered
- ClinVar has no submissions for any variant at this position. PM5 candidate search found no same-residue comparator variants.
Sources
clinvar ↗pm5_candidates
PS2 N/ANo de novo observation with confirmed maternity and paternity has been reported for NM_002742.3:c.2130A>C in any literature or database. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar and has not been reported in any publication.
PS3 N/ANo well-established in vitro or in vivo functional studies demonstrating a damaging effect for NM_002742.3:c.2130A>C are available. OncoKB reports an unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect. No variant-specific functional studies identified.
Still missing
- Functional characterization of p.Glu710Asp has not been performed.
Sources
PM5 N/ANo pathogenic missense variant at amino acid residue Glu710 has been identified. PM5 requires a different pathogenic amino acid change at the same residue, which is unavailable. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found zero same-residue comparator variants in ClinVar.
Sources
pm5_candidates
PM6 N/ANo de novo observation has been reported for NM_002742.3:c.2130A>C, with or without confirmation of maternity/paternity. This variant is absent from all clinical and literature sources. Details ▾Hide ▴
Evidence considered
- Variant not reported in ClinVar or any reviewed publication.
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing algorithms predict no impact. NM_002742.3:c.2130A>C is a missense variant (p.Glu710Asp) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- not a synonymous change.
PS5 N/APS5 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. PRKD1-associated disease (syndromic CHD with ectodermal dysplasia) is autosomal dominant; no trans configuration data are available. Details ▾Hide ▴
Evidence considered
- PRKD1 disease mechanism is autosomal dominant per germline literature.
Identifiers
- Gene
- PRKD1
- Transcript
- NM_002742.3
- Coding (HGVS c.)
- NM_002742.3:c.2130A>C
- Protein (HGVS p.)
- NP_002733.2:p.(Glu710Asp)
- GRCh38
- chr14:29599063 T>G
- GRCh37
- chr14:30068269 T>G
Gene diagram
Every interpreted variant in PRKD1, mapped onto the exon structure of NM_002742.3. Select a row to find it on the plot.
PRKD1NM_002742.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PRKD1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.744
- BayesDel
- 0.117
How the predictions were used
PP3 SupportingREVEL score of 0.744 exceeds the commonly used threshold of 0.7 for pathogenic prediction, supporting a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score of 0.117 does not independently support pathogenicity, but the REVEL score provides computational evidence of a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.744 (≥0.7 threshold).
- SpliceAI max delta: 0.00 (no splice impact).
- BayesDel score: 0.117.
Still missing
- BayesDel score is discordant with REVEL prediction.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score of 0.744 predicts a deleterious effect rather than no impact. Therefore BP4 does not apply. Details ▾Hide ▴
Evidence considered
- REVEL score 0.744 suggests damaging effect
- inconsistent with BP4 which requires evidence of no impact.
Sources
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing algorithms predict no impact. NM_002742.3:c.2130A>C is a missense variant (p.Glu710Asp) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- not a synonymous change.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.744. BayesDel score = 0.117431.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002742.3%3Ac.2130A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-30068269-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-29599063-T-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-29599063-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002742.3%3Ac.2130…
- OncoKB ↗www.oncokb.org/gene/PRKD1/E710D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PRKD1+c.2130A%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.744. BayesDel score = 0.117431.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRKD1, a serine/threonine kinase, is mutated in salivary gland carcinomas.
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.