17-68523716-CT-CTT

Position:

chr17-68523716-CT-CTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_002734.5(PRKAR1A):c.349-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,608,220 control chromosomes in the GnomAD database, including 42,341 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 3943 hom., cov: 26)

Exomes 𝑓: 0.23 ( 38398 hom. )

Consequence

PRKAR1A
NM_002734.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.71

Variant links:

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 links:

ENSG00000267009 (HGNC:):

ENSG00000267009 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 17-68523716-C-CT is Benign according to our data. Variant chr17-68523716-C-CT is described in ClinVar as [Benign]. Clinvar id is 41046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_002734.5 link	c.349-5dupT		splice_region_variant, intron_variant		ENST00000589228.6	NP_002725.1	P10644-1B2R5T5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6 link	c.349-5dupT		splice_region_variant, intron_variant		1	NM_002734.5	ENSP00000464977.2		P10644-1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34355

AN:

151976

Hom.:

3944

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.267

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.214

GnomAD3 exomes

AF:

0.220

AC:

55318

AN:

250992

Hom.:

6380

AF XY:

0.225

AC XY:

30563

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.243

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.148

Gnomad SAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.227

AC:

330696

AN:

1456126

Hom.:

38398

Cov.:

AF XY:

0.229

AC XY:

166243

AN XY:

724672

show subpopulations

Gnomad4 AFR exome

AF:

0.238

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.196

Gnomad4 EAS exome

AF:

0.223

Gnomad4 SAS exome

AF:

0.270

Gnomad4 FIN exome

AF:

0.257

Gnomad4 NFE exome

AF:

0.226

Gnomad4 OTH exome

AF:

0.221

GnomAD4 genome

AF:

0.226

AC:

34366

AN:

152094

Hom.:

3943

Cov.:

AF XY:

0.226

AC XY:

16824

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.173

Gnomad4 ASJ

AF:

0.198

Gnomad4 EAS

AF:

0.170

Gnomad4 SAS

AF:

0.261

Gnomad4 FIN

AF:

0.267

Gnomad4 NFE

AF:

0.228

Gnomad4 OTH

AF:

0.212

Alfa

AF:

0.223

Hom.:

833

Bravo

AF:

0.218

Asia WGS

AF:

0.211

AC:

735

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carney complex, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Acrodysostosis 1 with or without hormone resistance

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Acrodysostosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Carney complex

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over