17-68512233-G-T

Position:

• chr17-68512233-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000358598.6(PRKAR1A):​c.-7+91G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 153,836 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.019 (0 hom.)
• Consequence: PRKAR1A ENST00000358598.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.322

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]

ENSG00000267009 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-68512233-G-T is Benign according to our data. Variant chr17-68512233-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1339610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.011 (1678/152222) while in subpopulation NFE AF= 0.0158 (1074/67994). AF 95% confidence interval is 0.015. There are 18 homozygotes in gnomad4. There are 811 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1678 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAR1A	NM_001278433.2	c.-6-3161G>T		intron_variant			NP_001265362.1
PRKAR1A	NM_001369389.1	c.-140+91G>T		intron_variant			NP_001356318.1
PRKAR1A	NM_212471.3	c.-7+91G>T		intron_variant			NP_997636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000358598.6	c.-7+91G>T		intron_variant		1		ENSP00000351410.1
PRKAR1A	ENST00000589017.6	c.-140+91G>T		intron_variant		3		ENSP00000465445.2
PRKAR1A	ENST00000592800.6	c.-7+91G>T		intron_variant		2		ENSP00000466314.2
ENSG00000267009	ENST00000590353.1	n.174-3161G>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1677 AN: 152104 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.0186 AC: 30 AN: 1614 Hom.: 0 Cov.: 0 AF XY: 0.0162 AC XY: 19 AN XY: 1176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0110 AC: 1678 AN: 152222 Hom.: 18 Cov.: 32 AF XY: 0.0109 AC XY: 811 AN XY: 74430

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0128 Hom.: 2

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.0
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs78919109; hg19: chr17-66508374;