rs35635531

Positions:

• chr19-14093767-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_002730.4(PRKACA):​c.791C>G​(p.Ser264Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: PRKACA NM_002730.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.80

Genes affected

PRKACA (HGNC:9380): (protein kinase cAMP-activated catalytic subunit alpha) This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. 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. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing's syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKACA. . Gene score misZ 2.9714 (greater than the threshold 3.09). Trascript score misZ 3.8384 (greater than threshold 3.09). GenCC has associacion of gene with cardioacrofacial dysplasia 1, pigmented nodular adrenocortical disease, primary, 4.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKACA	NM_002730.4	c.791C>G	p.Ser264Cys	missense_variant	9/10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.1019C>G	p.Ser340Cys	missense_variant	9/10		NP_001291278.1
PRKACA	NM_207518.3	c.767C>G	p.Ser256Cys	missense_variant	9/10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.791C>G	p.Ser264Cys	missense_variant	9/10	1	NM_002730.4	ENSP00000309591	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250718 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727032

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000513

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.00

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: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D;.
Sift4G	Uncertain	0.029	D;D
Polyphen		0.0020	B;P
Vest4		0.66
MVP		0.69
MPC		1.9
ClinPred		0.57	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.64
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35635531; hg19: chr19-14204579;