ENST00000358598.6:c.-7+91G>T

Variant names:

• chr17-68512233-G-T
• rs78919109
• ENST00000358598.6:c.-7+91G>T

Variant summary

Our verdict is Benign. The variant received -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
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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 17-68512233-G-T is Benign according to our data. Variant chr17-68512233-G-T is described in ClinVar as Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1678 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358598.6. 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_001278433.2		c.-6-3161G>T		intron	N/A	NP_001265362.1	B2R5T5
	PRKAR1A	NM_001369389.1		c.-140+91G>T		intron	N/A	NP_001356318.1	P10644-1
	PRKAR1A	NM_212471.3		c.-7+91G>T		intron	N/A	NP_997636.1	P10644-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1A	ENST00000358598.6	TSL:1	c.-7+91G>T		intron	N/A	ENSP00000351410.1	P10644-1
	PRKAR1A	ENST00000589017.6	TSL:3	c.-140+91G>T		intron	N/A	ENSP00000465445.2	P10644-1
	PRKAR1A	ENST00000592800.6	TSL:2	c.-7+91G>T		intron	N/A	ENSP00000466314.2	K7EM13

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

African (AFR) AF: 0.00 AC: 0 AN: 18

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10

East Asian (EAS) AF: 0.00 AC: 0 AN: 46

South Asian (SAS) AF: 0.00 AC: 0 AN: 62

European-Finnish (FIN) AF: 0.0277 AC: 14 AN: 506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 12

European-Non Finnish (NFE) AF: 0.0173 AC: 15 AN: 868

Other (OTH) AF: 0.0116 AC: 1 AN: 86

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

African (AFR) AF: 0.00265 AC: 110 AN: 41548

American (AMR) AF: 0.0133 AC: 203 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4818

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1074 AN: 67994

Other (OTH) AF: 0.0123 AC: 26 AN: 2106

Alfa AF: 0.0128 Hom.: 2

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.0
DANN	Benign	0.72
PhyloP100		-0.32
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs78919109; hg19: chr17-66508374;