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).1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level.2 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.3 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.4 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.5
PRKD1
Final classification
VUS
PRKD1 c.2130A>C · p.Glu710Asp
PRKD1
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).
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.
Classification rationale
PM2PP3
VUS
PRKD1 c.2130A>C
PM2 + PP3
→
VUS
1
pvs1_gene_context
3
revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_002742.3 · variants mapped to exon structure
PRKD1
NM_002742.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 16 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
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.
REVEL score: 0.744 (≥0.7 threshold).SpliceAI max delta: 0.00 (no splice impact).BayesDel score: 0.117.
Assessed · not applied
Pathogenic
PS4
No case-control studies or enriched prevalence data are available.
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.
PP1
No co-segregation data are available for NM_002742.3:c.2130A>C.
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.
PP4
No patient phenotype or family history data are available for the individual carrying NM_002742.3:c.2130A>C.
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.
Benign
BA1
NM_002742.3:c.2130A>C is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada).
BS1
NM_002742.3:c.2130A>C is absent from all population databases.
BS2
No observations of NM_002742.3:c.2130A>C in healthy adult individuals have been reported.
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.
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.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
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.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene product.
BP5
No observation of NM_002742.3:c.2130A>C in a case with an alternate molecular basis for disease has been reported.
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.
N/A · 7
PVS1 · PS1 · PS2 · PS3 · PM5 · PM6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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 / ?
0 hom
0 hom
Not observed in any ancestry group.
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.
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
Unknown Oncogenic Effect
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.
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