Genetic Variant PRKAR1B:p.Val340Met (chr7-550558-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001164760.2(PRKAR1B):c.1018G>A(p.Val340Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,599,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PRKAR1B
NM_001164760.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33

Publications

1 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20796931).

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2 link	c.1018G>A	p.Val340Met	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.1018G>A	p.Val340Met	missense_variant	Exon 11 of 11	5	NM_001164760.2	ENSP00000440449.1		P31321

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000309

AC:

AN:

229412

AF XY:

0.000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000633

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000578

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.000359

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.000251

AC:

363

AN:

1447180

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

171

AN XY:

719342

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32780

American (AMR)

AF:

0.0000717

AC:

AN:

41856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25558

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00

AC:

AN:

84678

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

51332

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.000265

AC:

293

AN:

1106422

Other (OTH)

AF:

0.000168

AC:

AN:

59540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000309

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68014

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000898

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000276

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D;D;D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;.;.;.;.

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.0

M;M;M;M;M

PhyloP100

7.3

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

1.0

D;D;D;D;D

Vest4

0.75

MVP

0.99

MPC

1.2

ClinPred

0.30

GERP RS

4.7

Varity_R

0.39

gMVP

0.67

Mutation Taster

=0/100

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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7-550558-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over