19-14093146-T-C

Position:

• chr19-14093146-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_002730.4(PRKACA):​c.1022A>G​(p.Asn341Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PRKACA NM_002730.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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 -5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07768002).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKACA	NM_002730.4	c.1022A>G	p.Asn341Ser	missense_variant	10/10	ENST00000308677.9	NP_002721.1
PRKACA	NM_001304349.2	c.1250A>G	p.Asn417Ser	missense_variant	10/10		NP_001291278.1
PRKACA	NM_207518.3	c.998A>G	p.Asn333Ser	missense_variant	10/10		NP_997401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKACA	ENST00000308677.9	c.1022A>G	p.Asn341Ser	missense_variant	10/10	1	NM_002730.4	ENSP00000309591	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248900 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134764

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: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458884 Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5 AN XY: 725728

Gnomad4 AFR exome AF: 0.00

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: 0.00000901

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardioacrofacial dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 26, 2023

The PRKACA c.1022A>G (p.Asn341Ser) variant was identified at a near heterozygous allelic fraction. The PRKACA c.1022A>G (p.Asn341Ser) variant, to our knowledge, has not been reported in the medical literature. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that the variant does not impact PRKACA function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.14
Sift	Benign	0.28	T;.
Sift4G	Benign	0.81	T;T
Polyphen		0.0	B;B
Vest4		0.055
MutPred		0.14		Gain of phosphorylation at N341 (P = 0.0471);.;
MVP		0.52
MPC		0.80
ClinPred		0.10	T
GERP RS		-0.60
Varity_R		0.15
gMVP		0.39

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: rs775739774; hg19: chr19-14203958;