chr17-68512539-C-A

Variant names:

• chr17-68512539-C-A
• rs886053305
• NM_002734.5:c.-16C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_002734.5(PRKAR1A):​c.-16C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 154,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: PRKAR1A NM_002734.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 0.543
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000526 (80/152186) while in subpopulation NFE AF = 0.000338 (23/67978). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 80 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.-16C>A		5_prime_UTR	Exon 1 of 11	NP_002725.1	B2R5T5
	PRKAR1A	NM_001276289.2		c.-149C>A		5_prime_UTR	Exon 1 of 12	NP_001263218.1	P10644-1
	PRKAR1A	NM_212472.2		c.-47C>A		5_prime_UTR	Exon 1 of 11	NP_997637.1	B2R5T5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1A	ENST00000589228.6	TSL:1 MANE Select	c.-16C>A		5_prime_UTR	Exon 1 of 11	ENSP00000464977.2	P10644-1
	PRKAR1A	ENST00000536854.6	TSL:1	c.-149C>A		5_prime_UTR	Exon 1 of 12	ENSP00000445625.1	P10644-1
	PRKAR1A	ENST00000358598.6	TSL:1	c.-7+397C>A		intron	N/A	ENSP00000351410.1	P10644-1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000759 AC: 2 AN: 2636 Hom.: 0 Cov.: 0 AF XY: 0.00108 AC XY: 2 AN XY: 1856

African (AFR) AF: 0.00 AC: 0 AN: 38

American (AMR) AF: 0.00 AC: 0 AN: 28

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 36

East Asian (EAS) AF: 0.00 AC: 0 AN: 100

South Asian (SAS) AF: 0.00 AC: 0 AN: 224

European-Finnish (FIN) AF: 0.00259 AC: 1 AN: 386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.000574 AC: 1 AN: 1742

Other (OTH) AF: 0.00 AC: 0 AN: 76

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74414

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00528 AC: 56 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67978

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Acrodysostosis 1 with or without hormone resistance (1)
-	1	-	Carney complex, type 1 (1)
-	-	1	PRKAR1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		0.54
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886053305; hg19: chr17-66508680;