rs724160013

Variant names:

• chr19-14097621-G-GCAC
• rs724160013
• NM_002730.4:c.597_599dupGTG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP3 PP5

The NM_001304349.2(PRKACA):​c.825_827dupGTG​(p.Leu275_Cys276insTrp) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C276C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKACA NM_001304349.2 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.71
• Publications: 1 publications found

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]

PRKACA Gene-Disease associations (from GenCC):

• cardioacrofacial dysplasia 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pigmented nodular adrenocortical disease, primary, 4

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000295841 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001304349.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-14097621-G-GCAC is Pathogenic according to our data. Variant chr19-14097621-G-GCAC is described in ClinVar as Pathogenic. ClinVar VariationId is 162471.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304349.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	NM_002730.4	MANE Select	c.597_599dupGTG	p.Leu199_Cys200insTrp	disruptive_inframe_insertion	Exon 7 of 10	NP_002721.1
	PRKACA	NM_001304349.2		c.825_827dupGTG	p.Leu275_Cys276insTrp	disruptive_inframe_insertion	Exon 7 of 10	NP_001291278.1
	PRKACA	NM_207518.3		c.573_575dupGTG	p.Leu191_Cys192insTrp	disruptive_inframe_insertion	Exon 7 of 10	NP_997401.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	ENST00000308677.9	TSL:1 MANE Select	c.597_599dupGTG	p.Leu199_Cys200insTrp	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000309591.3
	PRKACA	ENST00000350356.7	TSL:2	c.825_827dupGTG	p.Leu275_Cys276insTrp	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000513361.1
	PRKACA	ENST00000589994.6	TSL:2	c.573_575dupGTG	p.Leu191_Cys192insTrp	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000466651.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pigmented nodular adrenocortical disease, primary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs724160013; hg19: chr19-14208433; COSMIC: COSV58069871;