rs387906694

Variant names:

• chr17-68530307-G-C
• rs387906694
• NM_002734.5:c.1004G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-68530307-G-C
• chr17-68530307-G-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_002734.5(PRKAR1A):​c.1004G>C​(p.Arg335Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAR1A NM_002734.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 3 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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_002734.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-68530306-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 17-68530307-G-C is Pathogenic according to our data. Variant chr17-68530307-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29909.Status of the report is no_assertion_criteria_provided, 0 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.1004G>C	p.Arg335Pro	missense	Exon 11 of 11	NP_002725.1	B2R5T5
	PRKAR1A	NM_001276289.2		c.1004G>C	p.Arg335Pro	missense	Exon 12 of 12	NP_001263218.1	P10644-1
	PRKAR1A	NM_001278433.2		c.1004G>C	p.Arg335Pro	missense	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.1004G>C	p.Arg335Pro	missense	Exon 11 of 11	ENSP00000464977.2	P10644-1
	PRKAR1A	ENST00000358598.6	TSL:1	c.1004G>C	p.Arg335Pro	missense	Exon 11 of 11	ENSP00000351410.1	P10644-1
	PRKAR1A	ENST00000536854.6	TSL:1	c.1004G>C	p.Arg335Pro	missense	Exon 12 of 12	ENSP00000445625.1	P10644-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acrodysostosis 1 with or without hormone resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.76		Loss of MoRF binding (P = 0.001)
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906694; hg19: chr17-66526448;