chr19-14097604-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_002730.4(PRKACA):​c.617T>G​(p.Leu206Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

PRKACA
NM_002730.4 missense

Scores

8
7
4

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 9.09
Variant links:
Genes affected
PRKACA (HGNC:9380): (protein kinase cAMP-activated catalytic subunit alpha) This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing's syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKACA. . Gene score misZ 2.9714 (greater than the threshold 3.09). Trascript score misZ 3.8384 (greater than threshold 3.09). GenCC has associacion of gene with cardioacrofacial dysplasia 1, pigmented nodular adrenocortical disease, primary, 4.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 19-14097604-A-C is Pathogenic according to our data. Variant chr19-14097604-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91945.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-14097604-A-C is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKACANM_002730.4 linkuse as main transcriptc.617T>G p.Leu206Arg missense_variant 7/10 ENST00000308677.9 NP_002721.1
PRKACANM_001304349.2 linkuse as main transcriptc.845T>G p.Leu282Arg missense_variant 7/10 NP_001291278.1
PRKACANM_207518.3 linkuse as main transcriptc.593T>G p.Leu198Arg missense_variant 7/10 NP_997401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKACAENST00000308677.9 linkuse as main transcriptc.617T>G p.Leu206Arg missense_variant 7/101 NM_002730.4 ENSP00000309591 P1P17612-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

ACTH-independent adrenal Cushing syndrome, somatic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2014- -
Pigmented nodular adrenocortical disease, primary, 4 Pathogenic:1
Pathogenic, no assertion criteria providedresearchInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenMar 13, 2014- -
not provided Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyRichard Lifton Laboratory, Yale University School of Medicine-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.43
T;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;T
M_CAP
Benign
0.084
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
0.90
L;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-5.2
D;.;.
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.99
MutPred
0.86
Gain of methylation at L206 (P = 0.0234);.;.;
MVP
0.92
MPC
2.6
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.98
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386352352; hg19: chr19-14208416; COSMIC: COSV58066423; API