17-68515400-A-G

Position:

• chr17-68515400-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

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, single submitter P:2 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_002734.5 (PRKAR1A) was described as [Likely_pathogenic] in ClinVar as 3222769
• 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_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1A	NM_002734.5	c.1A>G	p.Met1?	start_lost	2/11	ENST00000589228.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1A	ENST00000589228.6	c.1A>G	p.Met1?	start_lost	2/11	1	NM_002734.5	P1
	ENST00000590353.1	n.180A>G		non_coding_transcript_exon_variant	2/6	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carney complex, type 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 12, 2000	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2019

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
MutationTaster	Benign	1.0	D;D;D;D;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;