rs374377380

Variant names:

• chr3-48751593-C-T
• rs374377380
• NM_004157.4:c.1207G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004157.4(PRKAR2A):​c.1207G>A​(p.Gly403Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,611,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PRKAR2A NM_004157.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• Publications: 6 publications found

Genes affected

PRKAR2A (HGNC:9391): (protein kinase cAMP-dependent type II regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. This subunit can be phosphorylated by the activated catalytic subunit. It may interact with various A-kinase anchoring proteins and determine the subcellular localization of cAMP-dependent protein kinase. This subunit has been shown to regulate protein transport from endosomes to the Golgi apparatus and further to the endoplasmic reticulum (ER). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR2A	NM_004157.4	MANE Select	c.1207G>A	p.Gly403Arg	missense	Exon 11 of 11	NP_004148.1	P13861-1
	PRKAR2A	NM_001321982.2		c.1207G>A	p.Gly403Arg	missense	Exon 11 of 12	NP_001308911.1	A0A024R2W3
	PRKAR2A	NM_001321983.2		c.1141G>A	p.Gly381Arg	missense	Exon 10 of 10	NP_001308912.1	P13861-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAR2A	ENST00000265563.13	TSL:1 MANE Select	c.1207G>A	p.Gly403Arg	missense	Exon 11 of 11	ENSP00000265563.8	P13861-1
	PRKAR2A	ENST00000296446.12	TSL:1	c.1141G>A	p.Gly381Arg	missense	Exon 10 of 10	ENSP00000296446.8	P13861-2
	PRKAR2A	ENST00000706572.1		c.1207G>A	p.Gly403Arg	missense	Exon 11 of 12	ENSP00000516457.1	A0A9L9PXM7

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000797 AC: 20 AN: 250934 AF XY: 0.0000664

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000225 AC: 328 AN: 1459476 Hom.: 0 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 725658

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5160

European-Non Finnish (NFE) AF: 0.000292 AC: 324 AN: 1110614

Other (OTH) AF: 0.0000498 AC: 3 AN: 60264

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74338

African (AFR) AF: 0.000121 AC: 5 AN: 41444

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.15
MutPred		0.45		Gain of solvent accessibility (P = 0.019)
MVP		0.71
MPC		1.2
ClinPred		0.18	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.85
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374377380; hg19: chr3-48789026;