19-14097594-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_002730.4(PRKACA):c.627G>T(p.Glu209Asp) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKACA NM_002730.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.313

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKACA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACA	NM_002730.4	c.627G>T	p.Glu209Asp	missense_variant	7/10	ENST00000308677.9
PRKACA	NM_001304349.2	c.855G>T	p.Glu285Asp	missense_variant	7/10
PRKACA	NM_207518.3	c.603G>T	p.Glu201Asp	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACA	ENST00000308677.9	c.627G>T	p.Glu209Asp	missense_variant	7/10	1	NM_002730.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardioacrofacial dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	0.76	D;D;D;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.96		Loss of ubiquitination at K214 (P = 0.0992);.;.;
MVP		0.85
MPC		2.1
ClinPred		0.99	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-14208406;