chr19-14107354-G-A

Variant names:

• chr19-14107354-G-A
• rs56105247
• NM_002730.4:c.102C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002730.4(PRKACA):​c.102C>T​(p.Pro34Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,934 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: PRKACA NM_002730.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0110
• Publications: 4 publications found

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]

PRKACA Gene-Disease associations (from GenCC):

• cardioacrofacial dysplasia 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pigmented nodular adrenocortical disease, primary, 4

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-14107354-G-A is Benign according to our data. Variant chr19-14107354-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 708471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002730.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	NM_002730.4	MANE Select	c.102C>T	p.Pro34Pro	synonymous	Exon 2 of 10	NP_002721.1
	PRKACA	NM_001304349.2		c.330C>T	p.Pro110Pro	synonymous	Exon 2 of 10	NP_001291278.1
	PRKACA	NM_207518.3		c.78C>T	p.Pro26Pro	synonymous	Exon 2 of 10	NP_997401.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	ENST00000308677.9	TSL:1 MANE Select	c.102C>T	p.Pro34Pro	synonymous	Exon 2 of 10	ENSP00000309591.3
	PRKACA	ENST00000677951.1		c.-73C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000504551.1
	PRKACA	ENST00000536649.5	TSL:2	c.-73C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000503953.1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00238 AC: 599 AN: 251346 AF XY: 0.00237

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00354 AC: 5169 AN: 1461578 Hom.: 17 Cov.: 31 AF XY: 0.00346 AC XY: 2516 AN XY: 727124

African (AFR) AF: 0.000448 AC: 15 AN: 33470

American (AMR) AF: 0.00134 AC: 60 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86248

European-Finnish (FIN) AF: 0.00202 AC: 108 AN: 53420

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.00427 AC: 4744 AN: 1111816

Other (OTH) AF: 0.00296 AC: 179 AN: 60376

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74502

African (AFR) AF: 0.000890 AC: 37 AN: 41576

American (AMR) AF: 0.000784 AC: 12 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00351 AC: 239 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00217

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRKACA: BP4, BP7, BS2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		-0.011
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs56105247; hg19: chr19-14218166;