Variant classification summary

NM_002742.3:c.2130A>T

PRKD1 · NP_002733.2:p.(Glu710Asp) · NM_002742.3

GRCh37: chr14:30068269 T>A · GRCh38: chr14:29599063 T>A

Gene: PRKD1 Transcript: NM_002742.3

Final call

VUS

PM2 moderate

Variant details

Gene

PRKD1

Transcript

NM_002742.3

Protein

NP_002733.2:p.(Glu710Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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

3

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.

4

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.

5

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

6

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	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.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.	clinvar
PS5	Not assessed	No reputable source has classified NM_002742.3:c.2130A>T as pathogenic. The variant is absent from ClinVar.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not assessed	No cosegregation data are available for NM_002742.3:c.2130A>T in affected families.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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).
PP5	Not assessed	NM_002742.3:c.2130A>T is absent from ClinVar. No reputable source has classified this variant as pathogenic or likely pathogenic.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available on observation of NM_002742.3:c.2130A>T in healthy adults to exclude full disease penetrance.
BS3	Not assessed	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.	oncokb
BS4	Not assessed	No family segregation data are available to demonstrate lack of cosegregation with PRKD1-related disease.
BP1	Not met	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.
BP2	Not assessed	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No case has been reported in which an alternate molecular basis for disease was identified alongside NM_002742.3:c.2130A>T.
BP6	Not assessed	NM_002742.3:c.2130A>T is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	NM_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.

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