Variant chr1-84144497-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_182948.4(PRKACB):c.136G>A(p.Glu46Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000096 in 1,458,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PRKACB
NM_182948.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

Variant links:

Genes affected

PRKACB (HGNC:9381): (protein kinase cAMP-activated catalytic subunit beta) The protein encoded by this gene is a member of the serine/threonine protein kinase family. The encoded protein is a catalytic subunit of cAMP (cyclic AMP)-dependent protein kinase, which mediates signalling though cAMP. cAMP signaling is important to a number of processes, including cell proliferaton and differentiation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2014]

PRKACB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain Protein kinase (size 254) in uniprot entity KAPCB_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_182948.4

BP4

Computational evidence support a benign effect (MetaRNN=0.38854235).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACB	NM_182948.4 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	1/10	ENST00000370685.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACB	ENST00000370685.7 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	1/10	1	NM_182948.4		P22694-2
PRKACB	ENST00000370688.7 linkuse as main transcript	c.47-34680G>A		intron_variant		1			P22694-8
PRKACB	ENST00000370689.6 linkuse as main transcript	c.47-34680G>A		intron_variant		1		P1	P22694-1
PRKACB	ENST00000470673.5 linkuse as main transcript	n.176G>A		non_coding_transcript_exon_variant	1/7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

246724

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133588

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1458288

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.136G>A (p.E46K) alteration is located in exon 1 (coding exon 1) of the PRKACB gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glutamic acid (E) at amino acid position 46 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.021

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

M_CAP

Benign

0.027

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.90

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.18

REVEL

Benign

0.23

Sift

Uncertain

0.022

Sift4G

Benign

0.37

Polyphen

0.73

Vest4

0.58

MutPred

0.29

Gain of ubiquitination at E46 (P = 0.0045);

MVP

0.70

MPC

0.98

ClinPred

0.89

GERP RS

4.7

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over