rs117639566

Variant names:

• chr17-68524955-G-A
• rs117639566
• NM_002734.5:c.546G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-68524955-G-A
• chr17-68524955-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_002734.5(PRKAR1A):​c.546G>A​(p.Thr182Thr) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,607,116 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T182T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: PRKAR1A NM_002734.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.60
• Publications: 0 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

ENSG00000267009 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 17-68524955-G-A is Benign according to our data. Variant chr17-68524955-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000105 (16/152156) while in subpopulation EAS AF = 0.00232 (12/5174). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 AD gene.

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.546G>A	p.Thr182Thr	synonymous	Exon 6 of 11	NP_002725.1	B2R5T5
	PRKAR1A	NM_001276289.2		c.546G>A	p.Thr182Thr	synonymous	Exon 7 of 12	NP_001263218.1	P10644-1
	PRKAR1A	NM_001278433.2		c.546G>A	p.Thr182Thr	synonymous	Exon 6 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.546G>A	p.Thr182Thr	synonymous	Exon 6 of 11	ENSP00000464977.2	P10644-1
	PRKAR1A	ENST00000358598.6	TSL:1	c.546G>A	p.Thr182Thr	synonymous	Exon 6 of 11	ENSP00000351410.1	P10644-1
	PRKAR1A	ENST00000536854.6	TSL:1	c.546G>A	p.Thr182Thr	synonymous	Exon 7 of 12	ENSP00000445625.1	P10644-1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 251090 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000245 AC: 357 AN: 1454960 Hom.: 4 Cov.: 29 AF XY: 0.000258 AC XY: 187 AN XY: 724238

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.000358 AC: 16 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00823 AC: 326 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5742

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105982

Other (OTH) AF: 0.0000997 AC: 6 AN: 60170

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41508

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Carney complex, type 1 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Acrodysostosis 1 with or without hormone resistance (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.75
PhyloP100		9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs117639566; hg19: chr17-66521096; COSMIC: COSV62235614; COSMIC: COSV62235614;