rs281864779

Variant names:

• chr17-68515400-A-G
• rs281864779
• NM_002734.5:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_002734.5(PRKAR1A):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAR1A NM_002734.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.42

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 47 codons. Genomic position: 68515538. Lost 0.121 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-68515400-A-G is Pathogenic according to our data. Variant chr17-68515400-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1A	NM_002734.5	c.1A>G	p.Met1?	start_lost	Exon 2 of 11	ENST00000589228.6	NP_002725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.1A>G	p.Met1?	start_lost	Exon 2 of 11	1	NM_002734.5	ENSP00000464977.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carney complex, type 1 Pathogenic:2 Other:1

Dec 12, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PRKAR1A mRNA. The next in-frame methionine is located at codon 47. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with PRKAR1A-related conditions (PMID: 11115848, 19915019, 29909407). It has also been observed to segregate with disease in related individuals. This variant is also known as 88A>G. ClinVar contains an entry for this variant (Variation ID: 12669). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PRKAR1A function (PMID: 19915019). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 25, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is thought to lead to an alternate start codon downstream of the original start codon, and decrease binding of the PRKAR1A protein (Kirschner et al., 2000; Salpa et al., 2014); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22471738, 20850710, 24012779, 20829611, 11115848, 19915019, 27377598, 22112814, 21115159, 20358582, 16464939, 18241045, 29390296, 29237939, 29909407) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;T;T;T;T;T;.;.;T;T;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;.;D;D;.;.;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
PROVEAN	Benign	-0.75	.;N;N;.;.;N;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;D;D;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.82	.;P;P;.;P;P;.;.;.;.;.;P;.;.
Vest4		0.82, 0.82, 0.91, 0.73
MutPred		1.0		Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);Gain of glycosylation at T6 (P = 0.1567);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.81
gMVP		0.42

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: rs281864779; hg19: chr17-66511541;