chr1-84202743-G-C

Position:

• chr1-84202743-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_182948.4(PRKACB):​c.844G>C​(p.Gly282Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 254) in uniprot entity KAPCB_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_182948.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-84202743-G-C is Pathogenic according to our data. Variant chr1-84202743-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 989456.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-84202743-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKACB	NM_182948.4	c.844G>C	p.Gly282Arg	missense_variant	8/10	ENST00000370685.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKACB	ENST00000370685.7	c.844G>C	p.Gly282Arg	missense_variant	8/10	1	NM_182948.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardioacrofacial dysplasia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.;.;T;.;.;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;.;.;D;.;D;.;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;.;.;D;.;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D;D;.;D;D;.;.
Vest4		0.97
MutPred		0.94		Gain of methylation at G235 (P = 0.0422);Gain of methylation at G235 (P = 0.0422);.;.;.;.;.;.;.;.;.;.;
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1670492319; hg19: chr1-84668426;