rs8080306

Variant names:

• chr17-68512102-C-A
• rs8080306
• ENST00000358598.6:c.-47C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-68512102-C-A
• chr17-68512102-C-G

Variant summary

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

The NM_212471.3(PRKAR1A):​c.-47C>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 0.73 in 154,190 control chromosomes in the GnomAD database, including 41,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40657 hom., cov: 31)
  • Exomes 𝑓: 0.76 (658 hom.)
• Consequence: PRKAR1A NM_212471.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87
• Publications: 15 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

ENSG00000267009 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-68512102-C-A is Benign according to our data. Variant chr17-68512102-C-A is described in ClinVar as [Benign]. Clinvar id is 1295447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_001369389.1	c.-180C>A		5_prime_UTR_variant	Exon 1 of 12		NP_001356318.1
PRKAR1A	NM_212471.3	c.-47C>A		5_prime_UTR_variant	Exon 1 of 11		NP_997636.1
PRKAR1A	NM_001278433.2	c.-6-3292C>A		intron_variant	Intron 1 of 10		NP_001265362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000358598.6	c.-47C>A		5_prime_UTR_variant	Exon 1 of 11	1		ENSP00000351410.1
PRKAR1A	ENST00000589017.6	c.-180C>A		5_prime_UTR_variant	Exon 1 of 12	3		ENSP00000465445.2
PRKAR1A	ENST00000592800.6	c.-47C>A		5_prime_UTR_variant	Exon 1 of 10	2		ENSP00000466314.2
ENSG00000267009	ENST00000590353.1	n.174-3292C>A		intron_variant	Intron 1 of 5	4

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110827 AN: 151816 Hom.: 40634 Cov.: 31

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.751

GnomAD4 exome AF: 0.760 AC: 1714 AN: 2256 Hom.: 658 Cov.: 0 AF XY: 0.751 AC XY: 1217 AN XY: 1620

African (AFR) AF: 0.625 AC: 20 AN: 32

American (AMR) AF: 0.769 AC: 20 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 9 AN: 12

East Asian (EAS) AF: 0.956 AC: 65 AN: 68

South Asian (SAS) AF: 0.795 AC: 35 AN: 44

European-Finnish (FIN) AF: 0.741 AC: 246 AN: 332

Middle Eastern (MID) AF: 0.889 AC: 16 AN: 18

European-Non Finnish (NFE) AF: 0.751 AC: 1179 AN: 1570

Other (OTH) AF: 0.805 AC: 124 AN: 154

GnomAD4 genome AF: 0.730 AC: 110905 AN: 151934 Hom.: 40657 Cov.: 31 AF XY: 0.734 AC XY: 54494 AN XY: 74266

African (AFR) AF: 0.694 AC: 28775 AN: 41440

American (AMR) AF: 0.767 AC: 11719 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2481 AN: 3472

East Asian (EAS) AF: 0.959 AC: 4929 AN: 5140

South Asian (SAS) AF: 0.776 AC: 3741 AN: 4820

European-Finnish (FIN) AF: 0.761 AC: 8046 AN: 10570

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48726 AN: 67896

Other (OTH) AF: 0.750 AC: 1583 AN: 2112

Alfa AF: 0.725 Hom.: 96795

Bravo AF: 0.730

Asia WGS AF: 0.862 AC: 2998 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

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		-1.9
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.3
Mutation Taster		=300/0	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: rs8080306; hg19: chr17-66508243;