Variant classification summary

NM_002742.3:c.2130A>C

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

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

Gene: PRKD1 Transcript: NM_002742.3

Final call

VUS

PM2 supporting PP3 supporting

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>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).

2

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level.

3

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.

4

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.

5

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.

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	PVS1 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.	clinvar pm5_candidates
PS2	N/A	No de novo observation with confirmed maternity and paternity has been reported for NM_002742.3:c.2130A>C in any literature or database.
PS3	N/A	No 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.	oncokb
PS4	Not met	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.	clinvar
PS5	N/A	PS5 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.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	N/A	No 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.
PP1	Not met	No co-segregation data are available for NM_002742.3:c.2130A>C. No family studies including this variant have been reported.
PP2	Not met	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.	pvs1_gene_context
PP3	Met	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 spliceai bayesdel
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	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.	oncokb
BS4	Not met	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	Not met	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.	pvs1_gene_context
BP2	Not met	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	Not met	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.	revel spliceai bayesdel
BP5	Not met	No observation of NM_002742.3:c.2130A>C in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	NM_002742.3:c.2130A>C is absent from ClinVar and has not been reported as benign or likely benign by any reputable source.	clinvar
BP7	N/A	BP7 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.

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