rs745646679

Variant names:

• chr1-84182295-G-C
• rs745646679
• NM_182948.4:c.345G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_182948.4(PRKACB):​c.345G>C​(p.Gln115His) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,437,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000017 (1 hom.)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16558224).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKACB	NM_182948.4	c.345G>C	p.Gln115His	missense_variant	Exon 3 of 10	ENST00000370685.7	NP_891993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKACB	ENST00000370685.7	c.345G>C	p.Gln115His	missense_variant	Exon 3 of 10	1	NM_182948.4	ENSP00000359719.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000206 AC: 5 AN: 242214 Hom.: 0 AF XY: 0.0000305 AC XY: 4 AN XY: 131050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000287

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 24 AN: 1437316 Hom.: 1 Cov.: 30 AF XY: 0.0000126 AC XY: 9 AN XY: 714146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000570

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.345G>C (p.Q115H) alteration is located in exon 3 (coding exon 3) of the PRKACB gene. This alteration results from a G to C substitution at nucleotide position 345, causing the glutamine (Q) at amino acid position 115 to be replaced by a histidine (H). 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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T
Eigen	Benign	0.048
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.6	L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;.;N;.;N;N;N;N;N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.26	T;D;T;D;T;D;.;T;.;T;D;D;T;T;.;T;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;B;B;.;.;.;B;B;.;.;.;B;.;.;B;.;.
Vest4		0.48
MutPred		0.26		Loss of MoRF binding (P = 0.1022);Loss of MoRF binding (P = 0.1022);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.64
MPC		0.80
ClinPred		0.23	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.79

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: rs745646679; hg19: chr1-84647978;