NM_182948.4:c.245C>T

Variant names:

• chr1-84179234-C-T
• rs1662377427
• NM_182948.4:c.245C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_182948.4(PRKACB):​c.245C>T​(p.Thr82Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000254 in 1,576,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15940094).

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.245C>T	p.Thr82Ile	missense	Exon 2 of 10	NP_891993.1	P22694-2
	PRKACB	NM_001242857.3		c.125C>T	p.Thr42Ile	missense	Exon 5 of 13	NP_001229786.1	P22694-9
	PRKACB	NM_001242860.3		c.122C>T	p.Thr41Ile	missense	Exon 5 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.245C>T	p.Thr82Ile	missense	Exon 2 of 10	ENSP00000359719.3	P22694-2
	PRKACB	ENST00000614872.4	TSL:1	c.122C>T	p.Thr41Ile	missense	Exon 5 of 13	ENSP00000479722.1	P22694-6
	PRKACB	ENST00000370689.6	TSL:1	c.104C>T	p.Thr35Ile	missense	Exon 2 of 10	ENSP00000359723.2	P22694-1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151702 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1425152 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707522

African (AFR) AF: 0.00 AC: 0 AN: 32416

American (AMR) AF: 0.00 AC: 0 AN: 42348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.00 AC: 0 AN: 38626

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093676

Other (OTH) AF: 0.00 AC: 0 AN: 58418

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151702 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67858

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.063
Sift	Benign	0.081	T
Sift4G	Benign	0.13	T
Polyphen		0.021	B
Vest4		0.14
MutPred		0.30		Gain of catalytic residue at T35 (P = 0.007)
MVP		0.42
MPC		0.91
ClinPred		0.46	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.32
Mutation Taster		=88/12	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: rs1662377427; hg19: chr1-84644917;