rs200592054

Variant names:

• chr17-68525882-C-T
• rs200592054
• NM_002734.5:c.678C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-68525882-C-T
• chr17-68525882-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002734.5(PRKAR1A):​c.678C>T​(p.Ile226Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,526 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: PRKAR1A NM_002734.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.24
• Publications: 5 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-68525882-C-T is Benign according to our data. Variant chr17-68525882-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000296 (45/151828) while in subpopulation EAS AF = 0.00797 (41/5142). AF 95% confidence interval is 0.00604. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 45 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.678C>T	p.Ile226Ile	synonymous	Exon 7 of 11	NP_002725.1	B2R5T5
	PRKAR1A	NM_001276289.2		c.678C>T	p.Ile226Ile	synonymous	Exon 8 of 12	NP_001263218.1	P10644-1
	PRKAR1A	NM_001278433.2		c.678C>T	p.Ile226Ile	synonymous	Exon 7 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.678C>T	p.Ile226Ile	synonymous	Exon 7 of 11	ENSP00000464977.2	P10644-1
	PRKAR1A	ENST00000358598.6	TSL:1	c.678C>T	p.Ile226Ile	synonymous	Exon 7 of 11	ENSP00000351410.1	P10644-1
	PRKAR1A	ENST00000536854.6	TSL:1	c.678C>T	p.Ile226Ile	synonymous	Exon 8 of 12	ENSP00000445625.1	P10644-1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151708 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00795

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251324 AF XY: 0.000707

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1461698 Hom.: 3 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00766 AC: 304 AN: 39692

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111898

Other (OTH) AF: 0.000282 AC: 17 AN: 60384

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151828 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74178

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00797 AC: 41 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000453

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Carney complex, type 1 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Acrodysostosis 1 with or without hormone resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.7
DANN	Benign	0.74
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=93/7	polymorphism

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: rs200592054; hg19: chr17-66522023; COSMIC: COSV62235939; COSMIC: COSV62235939;