7-551448-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001164760.2(PRKAR1B):c.914G>A(p.Arg305His) variant causes a missense change. The variant allele was found at a frequency of 0.000155 in 1,557,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R305C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.02

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000526 (8/152134) while in subpopulation NFE AF= 0.0000882 (6/67996). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1B	NM_001164760.2	c.914G>A	p.Arg305His	missense_variant	10/11	ENST00000537384.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.914G>A	p.Arg305His	missense_variant	10/11	5	NM_001164760.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000617 AC: 10 AN: 161976 Hom.: 0 AF XY: 0.0000927 AC XY: 8 AN XY: 86332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000356

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000959

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 233 AN: 1405458 Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 96 AN XY: 693808

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.0000515

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74312

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000287 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.914G>A (p.R305H) alteration is located in exon 10 (coding exon 9) of the PRKAR1B gene. This alteration results from a G to A substitution at nucleotide position 914, causing the arginine (R) at amino acid position 305 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	0.19
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;D;D
Eigen	Benign	0.022
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;.;.;.
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.056	T;T;T;T;T
Sift4G	Uncertain	0.026	D;D;D;D;D
Polyphen		0.41	B;B;B;B;B
Vest4		0.85
MutPred		0.50		Loss of phosphorylation at S307 (P = 0.0589);Loss of phosphorylation at S307 (P = 0.0589);Loss of phosphorylation at S307 (P = 0.0589);Loss of phosphorylation at S307 (P = 0.0589);Loss of phosphorylation at S307 (P = 0.0589);
MVP		0.79
MPC		0.58
ClinPred		0.18	T
GERP RS		4.5
Varity_R		0.28
gMVP		0.65

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: rs748743633; hg19: chr7-591085;