17-68530405-C-T

Variant names:

• chr17-68530405-C-T
• rs387906692
• NM_002734.5:c.1102C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_002734.5(PRKAR1A):​c.1102C>T​(p.Arg368*) variant causes a stop gained 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001786630: Functional studies measuring the phosphorylation of cAMP responsive element-binding (CREB) protein, in forskolin-stimulated lymphocytic cell lines, showed that CREB phosphorylation was significantly reduced in cells from patients when compared with cells from controls (Linglart et al. 2011)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1A NM_002734.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.40
• Publications: 15 publications found

Genes affected

PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. 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. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

PRKAR1A Gene-Disease associations (from GenCC):

• Acrodysostosis 1 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• pigmented nodular adrenocortical disease, primary, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Carney complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial myxoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0384 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786630: Functional studies measuring the phosphorylation of cAMP responsive element-binding (CREB) protein, in forskolin-stimulated lymphocytic cell lines, showed that CREB phosphorylation was significantly reduced in cells from patients when compared with cells from controls (Linglart et al. 2011).; SCV002767741: Moderate functional evidence supporting abnormal protein function (PMID: 26405036; 21651393).; SCV004013552: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26405036, 27589370).; SCV000890174: Published functional studies demonstrate a damaging effect: gain of function variant leading to impaired ability of cAMP to dissociate subunits of PKA and repression of PKA activity (Linglert et al. 2011; Rhayem et al. 2015); SCV002244612: Experimental studies have shown that this premature translational stop signal affects PRKAR1A function (PMID: 21651393, 26405036).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-68530405-C-T is Pathogenic according to our data. Variant chr17-68530405-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002734.5. 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
	PRKAR1A	NM_002734.5	MANE Select	c.1102C>T	p.Arg368*	stop_gained	Exon 11 of 11	NP_002725.1	B2R5T5
	PRKAR1A	NM_001276289.2		c.1102C>T	p.Arg368*	stop_gained	Exon 12 of 12	NP_001263218.1	P10644-1
	PRKAR1A	NM_001278433.2		c.1102C>T	p.Arg368*	stop_gained	Exon 11 of 11	NP_001265362.1	B2R5T5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1A	ENST00000589228.6	TSL:1 MANE Select	c.1102C>T	p.Arg368*	stop_gained	Exon 11 of 11	ENSP00000464977.2	P10644-1
	PRKAR1A	ENST00000358598.6	TSL:1	c.1102C>T	p.Arg368*	stop_gained	Exon 11 of 11	ENSP00000351410.1	P10644-1
	PRKAR1A	ENST00000536854.6	TSL:1	c.1102C>T	p.Arg368*	stop_gained	Exon 12 of 12	ENSP00000445625.1	P10644-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Acrodysostosis 1 with or without hormone resistance (5)
4	-	-	not provided (4)
1	-	-	Carney complex, type 1 (1)
1	-	-	PRKAR1A-related disorder (1)
-	-	-	Carney complex;C1864846:Pigmented nodular adrenocortical disease, primary, 1;C3276228:Acrodysostosis 1 with or without hormone resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		2.4
Vest4		0.82
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906692; hg19: chr17-66526546; COSMIC: COSV56838441; COSMIC: COSV56838441;