0%
PRKD1c.2130A>TUncertain significance
Print report
Variant interpretation report

PRKD1 c.2130A>T, p.(Glu710Asp)

NM_002742.3:c.2130A>T NP_002733.2:p.(Glu710Asp) 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 PRKD1

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 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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

NM_002742.3:c.2130A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency in all large population databases is below the 0.1% generic ACMG PM2 threshold.

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 moderate; combination = 1 moderate, 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.

No listed criterion applied SpliceAI ↗
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 1 met · 7 not met · 15 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002742.3:c.2130A>T (p.Glu710Asp) is a missense variant in exon 15 of PRKD1.

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength.

Missense variants in PRKD1 are an established germline disease mechanism (PMID:32817298 reports de novo p.Gly592Arg and p.Arg603His causing syndromic congenital heart disease with ectodermal dysplasia); BP1 does not apply.

In silico predictors yield mixed results — REVEL 0.744 (damaging), BayesDel 0.117 (benign-leaning), SpliceAI 0.00 (neutral) — and do not meet the threshold for either PP3 or BP4.

No variant-specific functional data, de novo reports, cosegregation data, ClinVar classification, or case-control evidence are available for this variant.

With only one moderate criterion (PM2) met and no supporting or pathogenic moderate criteria, the variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.

Met · 1

PM2 ModerateNM_002742.3:c.2130A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency in all large population databases is below the 0.1% generic ACMG PM2 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 7 · evaluated, threshold not reached

PS1 No pathogenic or likely pathogenic variant at the same amino acid position (Glu710) with a different nucleotide change has been identified in ClinVar or the literature. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator identified
  • Variant absent from ClinVar
Still missing
  • No ClinVar data at codon 710 for comparison
Sources
clinvar ↗
PM1 The variant at codon 710 does not lie within a statistically significant mutational hotspot (Cancer Hotspots database negative). No evidence that it resides in a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue not significant
  • Exact variant not listed in hotspots
PP3 In silico predictors show mixed results. REVEL score is 0.744 (above 0.5 damaging threshold), but BayesDel score is 0.117 (below typical 0.27 damaging threshold, benign-leaning) and SpliceAI max delta is 0.00 (no predicted splice impact). Only one of three computational tools suggests a deleterious effect; multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.744 (damaging)
  • BayesDel 0.117 (benign-leaning)
  • SpliceAI max delta 0.00 (neutral)
Still missing
  • Lack of conservation scores (GERP
  • PhyloP)
  • No protein structural modeling data
Sources
revelbayesdelspliceai ↗
BA1 NM_002742.3:c.2130A>T is absent from gnomAD v2.1 and gnomAD v4.1. The allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_002742.3:c.2130A>T is absent from all gnomAD datasets. The allele frequency does not exceed the 0.3% BS1 threshold for generic ACMG. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP1 PRKD1 missense variants are an established disease mechanism. PMID:32817298 reports de novo missense mutations (p.Gly592Arg, p.Arg603His) causing a telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome. BP1 applies only when primarily truncating variants cause disease, which is not the case for PRKD1. Details ▾Hide ▴
Evidence considered
  • De novo missense mutations in PRKD1 cause syndromic CHD and ectodermal dysplasia
  • Missense is an established disease mechanism in PRKD1
BP4 In silico predictors show mixed results. REVEL score of 0.744 is consistent with a damaging effect, which contradicts the BP4 requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.117, benign-leaning) and SpliceAI (0.00, neutral) do not independently establish convergent benign predictions. Details ▾Hide ▴
Evidence considered
  • REVEL 0.744 (damaging)
  • BayesDel 0.117 (benign-leaning)
  • SpliceAI max delta 0.00 (neutral)
Sources
revelbayesdelspliceai ↗

Not assessed · 15 · no assessment recorded

PS2 No de novo testing data available for NM_002742.3:c.2130A>T. De novo mutations in PRKD1 have been reported at other residues (p.Gly592Arg, p.Arg603His; PMID:32817298) but not at Glu710. Details ▾Hide ▴
Still missing
  • No parental testing or trio data for this variant
PS3 No variant-specific functional studies have been identified for p.Glu710Asp in PRKD1. OncoKB reports no reviewed functional evidence for this variant. Literature search across PVS1 gene-context papers and evidence pipeline yielded no functional data for this specific change. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence
Still missing
  • No in vitro or in vivo functional characterization of p.Glu710Asp
Sources
oncokb ↗
PS4 No case-control or cohort data are available for NM_002742.3:c.2130A>T. The variant is absent from ClinVar and has not been reported in any curated disease or population cohorts. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no case reports identified
Still missing
  • No affected individual counts or case-control comparisons available
Sources
clinvar ↗
PM6 No de novo data are available for this specific variant. PRKD1 de novo missense mutations have been reported in the literature at other residues (p.Gly592Arg, p.Arg603His; PMID:32817298) but none at codon 710. Details ▾Hide ▴
Still missing
  • No parental testing or confirmed de novo status for this variant
PP1 No cosegregation data are available for NM_002742.3:c.2130A>T in affected families. Details ▾Hide ▴
Still missing
  • No family segregation analysis available
PP2 HCI prior data is unavailable for PRKD1; the gene is not in the supported gene list for PP2. Cannot assess whether PRKD1 has a low rate of benign missense variation to satisfy this criterion. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported
  • No custom PP2 score available
Still missing
  • No gene-level missense constraint metrics available (HCI prior/MTR/Z-score)
PP4 No patient phenotype information is available to assess whether this variant is found in an individual with a phenotype specific for PRKD1-related disease (congenital heart disease, ectodermal dysplasia, telangiectasia, brachydactyly). Details ▾Hide ▴
Still missing
  • No patient phenotype data provided
  • No HPO term or clinical description available
PP5 NM_002742.3:c.2130A>T is absent from ClinVar. No reputable source has classified this variant as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No external pathogenic classification available
Sources
clinvar ↗
BS2 No data are available on observation of NM_002742.3:c.2130A>T in healthy adults to exclude full disease penetrance. Details ▾Hide ▴
Still missing
  • No observation in healthy adult controls beyond gnomAD absence
BS3 No well-established functional studies demonstrate no deleterious effect for p.Glu710Asp in PRKD1. No functional data of any kind was identified for this specific variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific functional evidence
Still missing
  • No functional studies characterizing p.Glu710Asp
Sources
oncokb ↗
BS4 No family segregation data are available to demonstrate lack of cosegregation with PRKD1-related disease. Details ▾Hide ▴
Still missing
  • No family data for non-segregation analysis
BP2 No data are available on observation of NM_002742.3:c.2130A>T in trans with a known pathogenic PRKD1 variant. PRKD1-associated disease appears to follow autosomal dominant inheritance; trans observation would not be expected in a dominant disorder. Details ▾Hide ▴
Still missing
  • No trans-phase data available
  • criterion may be inherently inapplicable for dominant disorders
BP5 No case has been reported in which an alternate molecular basis for disease was identified alongside NM_002742.3:c.2130A>T. Details ▾Hide ▴
Still missing
  • No clinical cases with this variant and an alternate molecular diagnosis
BP6 NM_002742.3:c.2130A>T is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No external benign classification available
Sources
clinvar ↗
PS5 No reputable source has classified NM_002742.3:c.2130A>T as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No external classification from expert panel or reputable laboratory
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002742.3:c.2130A>T is a missense variant (p.Glu710Asp) in exon 15. It does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant bucket is 'other' and generic PVS1 framework application is not triggered per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution c.2130A>T
  • p.Glu710Asp
  • Variant bucket: other
  • Not a null variant or canonical splice site variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo same-residue ClinVar comparator variants at Glu710 with alternative amino acid substitutions were identified. PM5 candidate harvesting returned zero candidates and was assessed as not applicable. Details ▾Hide ▴
Evidence considered
  • PM5 mode: unknown
  • Zero same-residue candidate comparators identified
Sources
pm5_candidates
BP7 N/ANM_002742.3:c.2130A>T is a missense variant (p.Glu710Asp), not a synonymous variant. BP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous

Identifiers

Gene
PRKD1
Transcript
NM_002742.3
Coding (HGVS c.)
NM_002742.3:c.2130A>T
Protein (HGVS p.)
NP_002733.2:p.(Glu710Asp)
GRCh38
chr14:29599063 T>A
GRCh37
chr14:30068269 T>A

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…
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

SpliceAI acceptor lossat +62 bp
0.000
SpliceAI acceptor gainat +1 bp
0.000
SpliceAI donor lossat -36 bp
0.000
SpliceAI donor gainat -40 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.744
BayesDel
0.117

How the predictions were used

PP3 In silico predictors show mixed results. REVEL score is 0.744 (above 0.5 damaging threshold), but BayesDel score is 0.117 (below typical 0.27 damaging threshold, benign-leaning) and SpliceAI max delta is 0.00 (no predicted splice impact). Only one of three computational tools suggests a deleterious effect; multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.744 (damaging)
  • BayesDel 0.117 (benign-leaning)
  • SpliceAI max delta 0.00 (neutral)
Still missing
  • Lack of conservation scores (GERP
  • PhyloP)
  • No protein structural modeling data
Sources
revelbayesdelspliceai ↗
BP4 In silico predictors show mixed results. REVEL score of 0.744 is consistent with a damaging effect, which contradicts the BP4 requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.117, benign-leaning) and SpliceAI (0.00, neutral) do not independently establish convergent benign predictions. Details ▾Hide ▴
Evidence considered
  • REVEL 0.744 (damaging)
  • BayesDel 0.117 (benign-leaning)
  • SpliceAI max delta 0.00 (neutral)
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_002742.3:c.2130A>T is a missense variant (p.Glu710Asp), not a synonymous variant. BP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.744. BayesDel score = 0.117429.

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

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 = 0.117429.

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.