19-14097604-A-C

Position:

• chr19-14097604-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 9.09

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]

ACMG classification

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
PRKACA	NM_002730.4	c.617T>G	p.Leu206Arg	missense_variant	7/10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.845T>G	p.Leu282Arg	missense_variant	7/10		NP_001291278.1
PRKACA	NM_207518.3	c.593T>G	p.Leu198Arg	missense_variant	7/10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.617T>G	p.Leu206Arg	missense_variant	7/10	1	NM_002730.4	ENSP00000309591	P1

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

Submissions by phenotype

ACTH-independent adrenal Cushing syndrome, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2014

- -

Pigmented nodular adrenocortical disease, primary, 4 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Mar 13, 2014

- -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Richard 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

Other links and lift over

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