NM_002734.5:c.596G>A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP3_ModerateBS1_SupportingBS2_Supporting
The NM_002734.5(PRKAR1A):c.596G>A(p.Ser199Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S199S) has been classified as Likely benign.
Frequency
Consequence
NM_002734.5 missense
Scores
Clinical Significance
Conservation
Publications
- Acrodysostosis 1 with or without hormone resistanceInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- acrodysostosis with multiple hormone resistanceInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
- Carney complex, type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- pigmented nodular adrenocortical disease, primary, 1Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
- acrodysostosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Carney complexInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial atrial myxomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- primary pigmented nodular adrenocortical diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152032Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 251430 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727196 show subpopulations
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152032Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74264 show subpopulations
ClinVar
Submissions by phenotype
Acrodysostosis 1 with or without hormone resistance Uncertain:1
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not provided Uncertain:1
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Carney complex, type 1 Uncertain:1
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 199 of the PRKAR1A protein (p.Ser199Asn). This variant is present in population databases (rs755798109, gnomAD 0.03%). This missense change has been observed in individual(s) with prolactinoma (PMID: 34313605). ClinVar contains an entry for this variant (Variation ID: 469069). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRKAR1A protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
PRKAR1A-related disorder Uncertain:1
The PRKAR1A c.596G>A variant is predicted to result in the amino acid substitution p.Ser199Asn. This variant was reported in an individual with a pituitary adenoma (Martínez de LaPiscina et al 2021. PubMed ID: 34313605). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-66521941-G-A). It is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/469069/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at