10-51999127-T-C

Variant names:

• chr10-51999127-T-C
• rs2252101
• NM_006258.4:c.763-55357T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006258.4(PRKG1):​c.763-55357T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,148 control chromosomes in the GnomAD database, including 9,697 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 0.34 (9697 hom., cov: 33)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• Publications: 2 publications found

Genes affected

PRKG1 (HGNC:9414): (protein kinase cGMP-dependent 1) Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]

PRKG1 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 8

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.763-55357T>C		intron_variant	Intron 5 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.763-55357T>C		intron_variant	Intron 5 of 17	1	NM_006258.4	ENSP00000363092.5
PRKG1	ENST00000401604.8	c.718-55357T>C		intron_variant	Intron 5 of 17	5		ENSP00000384200.4
PRKG1	ENST00000645324.1	c.763-55357T>C		intron_variant	Intron 5 of 7			ENSP00000494124.1
PRKG1	ENST00000373976.9	c.763-55357T>C		intron_variant	Intron 5 of 6	3		ENSP00000363087.4

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52391 AN: 152030 Hom.: 9690 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.345 AC: 52419 AN: 152148 Hom.: 9697 Cov.: 33 AF XY: 0.346 AC XY: 25741 AN XY: 74380

African (AFR) AF: 0.213 AC: 8839 AN: 41534

American (AMR) AF: 0.413 AC: 6315 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1586 AN: 3470

East Asian (EAS) AF: 0.250 AC: 1294 AN: 5170

South Asian (SAS) AF: 0.390 AC: 1884 AN: 4828

European-Finnish (FIN) AF: 0.419 AC: 4425 AN: 10560

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26919 AN: 67982

Other (OTH) AF: 0.345 AC: 728 AN: 2112

Alfa AF: 0.325 Hom.: 2923

Bravo AF: 0.341

Asia WGS AF: 0.278 AC: 966 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.68
PhyloP100		0.036
Mutation Taster		=100/0	polymorphism (auto)

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: rs2252101; hg19: chr10-53758887;