chr1-84144401-G-C

Variant names:

• chr1-84144401-G-C
• NM_182948.4:c.40G>C

Variant summary

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

The NM_182948.4(PRKACB):​c.40G>C​(p.Gly14Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,976 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: 6.8e-7 (0 hom.)
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72
• 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 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.40G>C	p.Gly14Arg	missense	Exon 1 of 10	NP_891993.1	P22694-2
	PRKACB	NM_001300916.2		c.40G>C	p.Gly14Arg	missense	Exon 1 of 9	NP_001287845.1
	PRKACB	NM_002731.4		c.47-34776G>C		intron	N/A	NP_002722.1	B2RB89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKACB	ENST00000370685.7	TSL:1 MANE Select	c.40G>C	p.Gly14Arg	missense	Exon 1 of 10	ENSP00000359719.3	P22694-2
	PRKACB	ENST00000370689.6	TSL:1	c.47-34776G>C		intron	N/A	ENSP00000359723.2	P22694-1
	PRKACB	ENST00000370688.7	TSL:1	c.47-34776G>C		intron	N/A	ENSP00000359722.3	P22694-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460976 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726822

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

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111606

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Benign	0.32
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Pathogenic	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.58	T
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Polyphen		0.98	D
Vest4		0.80
MutPred		0.41		Gain of MoRF binding (P = 0.0217)
MVP		0.65
MPC		1.5
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.0058	Neutral
gMVP		0.47
Mutation Taster		=45/55	disease causing

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

hg19: chr1-84610084;