7-551436-T-G

Variant names:

• chr7-551436-T-G
• rs545787093
• NM_001164760.2:c.926A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001164760.2(PRKAR1B):​c.926A>C​(p.Asn309Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.73

Genes affected

PRKAR1B (HGNC:9390): (protein kinase cAMP-dependent type I regulatory subunit beta) The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-551436-T-G is Pathogenic according to our data. Variant chr7-551436-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3349891.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1979475). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.926A>C	p.Asn309Thr	missense_variant	Exon 10 of 11	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.926A>C	p.Asn309Thr	missense_variant	Exon 10 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

PRKAR1B-related disorder Pathogenic:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PRKAR1B c.926A>C variant is predicted to result in the amino acid substitution p.Asn309Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant was detected as de novo in an individual undergoing testing at PreventionGenetics (internal data). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.40
DEOGEN2	Uncertain	0.57	D;D;D;D;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.67	T;.;.;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.40	N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.30
MutPred		0.34		Gain of phosphorylation at N309 (P = 0.0042);Gain of phosphorylation at N309 (P = 0.0042);Gain of phosphorylation at N309 (P = 0.0042);Gain of phosphorylation at N309 (P = 0.0042);Gain of phosphorylation at N309 (P = 0.0042);
MVP		0.77
MPC		0.39
ClinPred		0.13	T
GERP RS		0.62
Varity_R		0.23
gMVP		0.35

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: rs545787093; hg19: chr7-591073;