chr7-551425-C-T

Position:

• chr7-551425-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001164760.2(PRKAR1B):​c.937G>A​(p.Val313Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000066 in 1,560,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: PRKAR1B NM_001164760.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02920854).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000722 (11/152250) while in subpopulation EAS AF= 0.000965 (5/5182). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 5 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 GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAR1B	NM_001164760.2	c.937G>A	p.Val313Met	missense_variant	10/11	ENST00000537384.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.937G>A	p.Val313Met	missense_variant	10/11	5	NM_001164760.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000149 AC: 25 AN: 168308 Hom.: 0 AF XY: 0.000189 AC XY: 17 AN XY: 89754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000751

Gnomad SAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000750

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.0000653 AC: 92 AN: 1408442 Hom.: 0 Cov.: 31 AF XY: 0.0000647 AC XY: 45 AN XY: 695524

Gnomad4 AFR exome AF: 0.0000611

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000771

Gnomad4 SAS exome AF: 0.000300

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.000154

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000372 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000913 AC: 10

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

Jun 23, 2023

The c.937G>A (p.V313M) 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 937, causing the valine (V) at amino acid position 313 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;D;D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;.;.;.;.
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.7	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.071	T;T;T;T;T
Polyphen		0.0060	B;B;B;B;B
Vest4		0.46
MVP		0.89
MPC		0.39
ClinPred		0.046	T
GERP RS		2.7
Varity_R		0.082
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148058026; hg19: chr7-591062;