chr1-84182252-C-T

Variant names:

• chr1-84182252-C-T
• rs1663748771
• NM_182948.4:c.302C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_182948.4(PRKACB):​c.302C>T​(p.Ser101Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKACB NM_182948.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.05
• 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: Likely_pathogenic. The variant received 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 1-84182252-C-T is Pathogenic according to our data. Variant chr1-84182252-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 989457.Status of the report is no_assertion_criteria_provided, 0 stars.

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.302C>T	p.Ser101Leu	missense	Exon 3 of 10	NP_891993.1	P22694-2
	PRKACB	NM_001242857.3		c.182C>T	p.Ser61Leu	missense	Exon 6 of 13	NP_001229786.1	P22694-9
	PRKACB	NM_001242860.3		c.179C>T	p.Ser60Leu	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.302C>T	p.Ser101Leu	missense	Exon 3 of 10	ENSP00000359719.3	P22694-2
	PRKACB	ENST00000614872.4	TSL:1	c.179C>T	p.Ser60Leu	missense	Exon 6 of 13	ENSP00000479722.1	P22694-6
	PRKACB	ENST00000370689.6	TSL:1	c.161C>T	p.Ser54Leu	missense	Exon 3 of 10	ENSP00000359723.2	P22694-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151878 Hom.: 0 Cov.: 31

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448534 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720462

⚠️ 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: 33052

American (AMR) AF: 0.00 AC: 0 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.00 AC: 0 AN: 84130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103842

Other (OTH) AF: 0.00 AC: 0 AN: 59768

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74138

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000625 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cardioacrofacial dysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.021	B
Vest4		0.83
MutPred		0.83		Loss of phosphorylation at S54 (P = 0.0485)
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.68
Mutation Taster		=43/57	disease causing (ClinVar)

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: rs1663748771; hg19: chr1-84647935;