chr1-84175057-G-A

Position:

• chr1-84175057-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000614872.4(PRKACB):​c.55+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: PRKACB ENST00000614872.4 splice_donor
• Scores: Splicing: ADA: 0.008707
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02141527 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACB	NM_182948.4	c.188-4120G>A		intron_variant		ENST00000370685.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACB	ENST00000370685.7	c.188-4120G>A		intron_variant		1	NM_182948.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1305200 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 642376

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: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

PRKACB-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2024

The PRKACB c.55+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. In the more commonly reported transcript (NM_182948.3), this variant is intronic (c.188-4120G>A). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0088	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	0.073
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0087
dbscSNV1_RF	Benign	0.046
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: rs991951661; hg19: chr1-84640740;