rs12728744

Variant names:

• chr1-84116872-A-G
• rs12728744
• ENST00000370689.6:c.46+38501A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000370689.6(PRKACB):​c.46+38501A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 152,248 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.029 (104 hom., cov: 32)
• Consequence: PRKACB ENST00000370689.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0289 (4403/152248) while in subpopulation NFE AF = 0.0415 (2820/68008). AF 95% confidence interval is 0.0402. There are 104 homozygotes in GnomAd4. There are 2230 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 104 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKACB	NM_002731.4	c.46+38501A>G		intron_variant	Intron 1 of 9		NP_002722.1
PRKACB	NM_001375576.1	c.46+38501A>G		intron_variant	Intron 1 of 8		NP_001362505.1
PRKACB	NM_207578.3	c.46+38501A>G		intron_variant	Intron 1 of 8		NP_997461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKACB	ENST00000370689.6	c.46+38501A>G		intron_variant	Intron 1 of 9	1		ENSP00000359723.2
PRKACB	ENST00000370688.7	c.46+38501A>G		intron_variant	Intron 1 of 8	1		ENSP00000359722.3

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4402 AN: 152130 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0864

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0196

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0289 AC: 4403 AN: 152248 Hom.: 104 Cov.: 32 AF XY: 0.0300 AC XY: 2230 AN XY: 74434

African (AFR) AF: 0.00645 AC: 268 AN: 41556

American (AMR) AF: 0.0165 AC: 253 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.0864 AC: 915 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0415 AC: 2820 AN: 68008

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0394 Hom.: 221

Bravo AF: 0.0231

Asia WGS AF: 0.00375 AC: 14 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.49
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12728744; hg19: chr1-84582555;