rs34988264

Variant names:

• chr19-14097452-AG-A
• rs34988264
• NM_002730.4:c.673delC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002730.4(PRKACA):​c.673delC​(p.Leu225TrpfsTer42) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKACA NM_002730.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKACA	NM_002730.4	c.673delC	p.Leu225TrpfsTer42	frameshift_variant	Exon 8 of 10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.901delC	p.Leu301TrpfsTer42	frameshift_variant	Exon 8 of 10		NP_001291278.1
PRKACA	NM_207518.3	c.649delC	p.Leu217TrpfsTer42	frameshift_variant	Exon 8 of 10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.673delC	p.Leu225TrpfsTer42	frameshift_variant	Exon 8 of 10	1	NM_002730.4	ENSP00000309591.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34988264; hg19: chr19-14208264;