rs3785905

Variant names:

• chr17-68527631-G-A
• rs3785905
• NM_002734.5:c.709-209G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002734.5(PRKAR1A):​c.709-209G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 523,032 control chromosomes in the GnomAD database, including 5,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1707 hom., cov: 32)
  • Exomes 𝑓: 0.14 (4042 hom.)
• Consequence: PRKAR1A NM_002734.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.214
• Publications: 7 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-68527631-G-A is Benign according to our data. Variant chr17-68527631-G-A is described in ClinVar as Benign. ClinVar VariationId is 677028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.709-209G>A		intron_variant	Intron 7 of 10	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.709-209G>A		intron_variant	Intron 7 of 10	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22381 AN: 151738 Hom.: 1706 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.144 AC: 53392 AN: 371174 Hom.: 4042 Cov.: 4 AF XY: 0.147 AC XY: 29188 AN XY: 198102

African (AFR) AF: 0.174 AC: 1862 AN: 10686

American (AMR) AF: 0.166 AC: 2624 AN: 15804

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 1305 AN: 11340

East Asian (EAS) AF: 0.168 AC: 4212 AN: 25118

South Asian (SAS) AF: 0.190 AC: 8078 AN: 42620

European-Finnish (FIN) AF: 0.108 AC: 2112 AN: 19582

Middle Eastern (MID) AF: 0.100 AC: 158 AN: 1574

European-Non Finnish (NFE) AF: 0.135 AC: 30070 AN: 223422

Other (OTH) AF: 0.141 AC: 2971 AN: 21028

GnomAD4 genome AF: 0.147 AC: 22384 AN: 151858 Hom.: 1707 Cov.: 32 AF XY: 0.148 AC XY: 10944 AN XY: 74172

African (AFR) AF: 0.171 AC: 7068 AN: 41414

American (AMR) AF: 0.158 AC: 2418 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3466

East Asian (EAS) AF: 0.171 AC: 881 AN: 5156

South Asian (SAS) AF: 0.198 AC: 955 AN: 4818

European-Finnish (FIN) AF: 0.106 AC: 1112 AN: 10488

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9081 AN: 67932

Other (OTH) AF: 0.137 AC: 289 AN: 2110

Alfa AF: 0.138 Hom.: 6297

Bravo AF: 0.154

Asia WGS AF: 0.189 AC: 656 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs3785905; hg19: chr17-66523772; COSMIC: COSV104423104;