chr19-14093172-C-T

Variant names:

• chr19-14093172-C-T
• rs370912699
• NM_002730.4:c.996G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_002730.4(PRKACA):​c.996G>A​(p.Glu332Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,796 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: PRKACA NM_002730.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.928
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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)

ENSG00000295841 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 19-14093172-C-T is Benign according to our data. Variant chr19-14093172-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.928 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	NM_002730.4	MANE Select	c.996G>A	p.Glu332Glu	synonymous	Exon 10 of 10	NP_002721.1	P17612-1
	PRKACA	NM_001304349.2		c.1224G>A	p.Glu408Glu	synonymous	Exon 10 of 10	NP_001291278.1	A0A8V8TL59
	PRKACA	NM_207518.3		c.972G>A	p.Glu324Glu	synonymous	Exon 10 of 10	NP_997401.1	P17612-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACA	ENST00000308677.9	TSL:1 MANE Select	c.996G>A	p.Glu332Glu	synonymous	Exon 10 of 10	ENSP00000309591.3	P17612-1
	PRKACA	ENST00000350356.7	TSL:2	c.1224G>A	p.Glu408Glu	synonymous	Exon 10 of 10	ENSP00000513361.1	A0A8V8TL59
	PRKACA	ENST00000589994.6	TSL:2	c.972G>A	p.Glu324Glu	synonymous	Exon 10 of 10	ENSP00000466651.1	P17612-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 248980 AF XY: 0.0000519

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461796 Hom.: 1 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 30

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.8
DANN	Benign	0.69
PhyloP100		0.93

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: rs370912699; hg19: chr19-14203984;