chr17-68530175-A-T

Variant names:

• chr17-68530175-A-T
• rs2302233
• NM_002734.5:c.974-102A>T

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.974-102A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,514,986 control chromosomes in the GnomAD database, including 37,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3008 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34357 hom.)
• Consequence: PRKAR1A NM_002734.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.144
• Publications: 6 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 17-68530175-A-T is Benign according to our data. Variant chr17-68530175-A-T is described in ClinVar as Benign. ClinVar VariationId is 1229416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002734.5. 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_002734.5	MANE Select	c.974-102A>T		intron	N/A	NP_002725.1
	PRKAR1A	NM_001276289.2		c.974-102A>T		intron	N/A	NP_001263218.1
	PRKAR1A	NM_001278433.2		c.974-102A>T		intron	N/A	NP_001265362.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR1A	ENST00000589228.6	TSL:1 MANE Select	c.974-102A>T		intron	N/A	ENSP00000464977.2
	PRKAR1A	ENST00000358598.6	TSL:1	c.974-102A>T		intron	N/A	ENSP00000351410.1
	PRKAR1A	ENST00000536854.6	TSL:1	c.974-102A>T		intron	N/A	ENSP00000445625.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29419 AN: 151970 Hom.: 3010 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.221 AC: 301429 AN: 1362898 Hom.: 34357 Cov.: 24 AF XY: 0.223 AC XY: 152544 AN XY: 683070

African (AFR) AF: 0.131 AC: 4087 AN: 31220

American (AMR) AF: 0.156 AC: 6937 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5032 AN: 25598

East Asian (EAS) AF: 0.165 AC: 6479 AN: 39198

South Asian (SAS) AF: 0.249 AC: 20865 AN: 83816

European-Finnish (FIN) AF: 0.257 AC: 13644 AN: 53048

Middle Eastern (MID) AF: 0.256 AC: 1238 AN: 4828

European-Non Finnish (NFE) AF: 0.226 AC: 231065 AN: 1023604

Other (OTH) AF: 0.211 AC: 12082 AN: 57146

GnomAD4 genome AF: 0.193 AC: 29413 AN: 152088 Hom.: 3008 Cov.: 32 AF XY: 0.194 AC XY: 14409 AN XY: 74336

African (AFR) AF: 0.133 AC: 5510 AN: 41484

American (AMR) AF: 0.161 AC: 2460 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3470

East Asian (EAS) AF: 0.146 AC: 758 AN: 5182

South Asian (SAS) AF: 0.237 AC: 1143 AN: 4816

European-Finnish (FIN) AF: 0.266 AC: 2806 AN: 10562

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15479 AN: 67982

Other (OTH) AF: 0.188 AC: 397 AN: 2110

Alfa AF: 0.212 Hom.: 445

Bravo AF: 0.183

Asia WGS AF: 0.185 AC: 646 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.84
CADD	Benign	2.0
DANN	Benign	0.47
PhyloP100		-0.14
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: rs2302233; hg19: chr17-66526316; COSMIC: COSV56836806; COSMIC: COSV56836806;