rs755081600

Variant names:

• chr1-84182233-A-G
• rs755081600
• NM_182948.4:c.283A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_182948.4(PRKACB):​c.283A>G​(p.Lys95Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

PRKACB (HGNC:9381): (protein kinase cAMP-activated catalytic subunit beta) The protein encoded by this gene is a member of the serine/threonine protein kinase family. The encoded protein is a catalytic subunit of cAMP (cyclic AMP)-dependent protein kinase, which mediates signalling though cAMP. cAMP signaling is important to a number of processes, including cell proliferaton and differentiation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2014]

PRKACB Gene-Disease associations (from GenCC):

• cardioacrofacial dysplasia 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.8044 (below the threshold of 3.09). Trascript score misZ: 2.3181 (below the threshold of 3.09). GenCC associations: The gene is linked to cardioacrofacial dysplasia 2, Ellis-van Creveld syndrome.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182948.4. 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
	PRKACB	NM_182948.4	MANE Select	c.283A>G	p.Lys95Glu	missense	Exon 3 of 10	NP_891993.1	P22694-2
	PRKACB	NM_001242857.3		c.163A>G	p.Lys55Glu	missense	Exon 6 of 13	NP_001229786.1	P22694-9
	PRKACB	NM_001242860.3		c.160A>G	p.Lys54Glu	missense	Exon 6 of 13	NP_001229789.1	P22694-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACB	ENST00000370685.7	TSL:1 MANE Select	c.283A>G	p.Lys95Glu	missense	Exon 3 of 10	ENSP00000359719.3	P22694-2
	PRKACB	ENST00000614872.4	TSL:1	c.160A>G	p.Lys54Glu	missense	Exon 6 of 13	ENSP00000479722.1	P22694-6
	PRKACB	ENST00000370689.6	TSL:1	c.142A>G	p.Lys48Glu	missense	Exon 3 of 10	ENSP00000359723.2	P22694-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243416 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439316 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715570

African (AFR) AF: 0.00 AC: 0 AN: 32742

American (AMR) AF: 0.0000230 AC: 1 AN: 43436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25646

East Asian (EAS) AF: 0.00 AC: 0 AN: 38838

South Asian (SAS) AF: 0.00 AC: 0 AN: 82096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098706

Other (OTH) AF: 0.0000168 AC: 1 AN: 59406

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.48
Sift	Benign	0.061	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.47		Loss of ubiquitination at K48 (P = 0.0103)
MVP		0.74
MPC		1.6
ClinPred		0.68	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.77
Mutation Taster		=50/50

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: rs755081600; hg19: chr1-84647916;