NM_001164760.2:c.1003C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001164760.2(PRKAR1B):c.1003C>T(p.Arg335Trp) 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 pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRKAR1B
NM_001164760.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.04

Publications

4 publications found

Variant links:

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]

PRKAR1B Gene-Disease associations (from GenCC):

Marbach-Schaaf neurodevelopmental syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
PRKAR1B-related neurodegenerative dementia with intermediate filaments
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRKAR1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity KAP1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 7-550573-G-A is Pathogenic according to our data. Variant chr7-550573-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1172535.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
PRKAR1B	NM_001164760.2 link	c.1003C>T	p.Arg335Trp	missense_variant	Exon 11 of 11	ENST00000537384.6	NP_001158232.1	P31321

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6 link	c.1003C>T	p.Arg335Trp	missense_variant	Exon 11 of 11	5	NM_001164760.2	ENSP00000440449.1		P31321

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

224182

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715972

African (AFR)

AF:

0.00

AC:

AN:

32504

American (AMR)

AF:

0.00

AC:

AN:

40810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.00

AC:

AN:

83944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103868

Other (OTH)

AF:

0.00

AC:

AN:

59212

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRKAR1B: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PRKAR1B-related neurodevelopmental disorder

Pathogenic:1

May 17, 2021

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Marbach-Schaaf neurodevelopmental syndrome

Pathogenic:1

Dec 23, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;.;.;.;.

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H;H;H;H

PhyloP100

2.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.8

D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.92

MutPred

0.90

Gain of catalytic residue at R335 (P = 0.0267);Gain of catalytic residue at R335 (P = 0.0267);Gain of catalytic residue at R335 (P = 0.0267);Gain of catalytic residue at R335 (P = 0.0267);Gain of catalytic residue at R335 (P = 0.0267);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

4.7

Varity_R

0.80

gMVP

0.94

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over