10-51153260-G-A

Variant names:

• chr10-51153260-G-A
• rs55806342
• NM_006258.4:c.408G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006258.4(PRKG1):​c.408G>A​(p.Pro136Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,612,374 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P136P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 31)
  • Exomes 𝑓: 0.020 (394 hom.)
• Consequence: PRKG1 NM_006258.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.08
• Publications: 8 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, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 10-51153260-G-A is Benign according to our data. Variant chr10-51153260-G-A is described in ClinVar as Benign. ClinVar VariationId is 220801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2627/152044) while in subpopulation NFE AF = 0.0235 (1599/67920). AF 95% confidence interval is 0.0226. There are 40 homozygotes in GnomAd4. There are 1305 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2627 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006258.4. 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
	PRKG1	NM_006258.4	MANE Select	c.408G>A	p.Pro136Pro	synonymous	Exon 2 of 18	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.363G>A	p.Pro121Pro	synonymous	Exon 2 of 18	NP_001091982.1	Q13976-1
	PRKG1	NM_001374782.1		c.408G>A	p.Pro136Pro	synonymous	Exon 2 of 7	NP_001361711.1	B1ALS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.408G>A	p.Pro136Pro	synonymous	Exon 2 of 18	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.363G>A	p.Pro121Pro	synonymous	Exon 2 of 18	ENSP00000384200.4	Q13976-1
	PRKG1	ENST00000645324.1		c.408G>A	p.Pro136Pro	synonymous	Exon 2 of 8	ENSP00000494124.1	A0A2R8Y507

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 151926 Hom.: 41 Cov.: 31

Gnomad AFR AF: 0.00515

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0172 AC: 4315 AN: 250736 AF XY: 0.0174

Gnomad AFR exome AF: 0.00502

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0202 AC: 29480 AN: 1460330 Hom.: 394 Cov.: 30 AF XY: 0.0202 AC XY: 14643 AN XY: 726482

African (AFR) AF: 0.00468 AC: 156 AN: 33364

American (AMR) AF: 0.0107 AC: 476 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 727 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00860 AC: 741 AN: 86190

European-Finnish (FIN) AF: 0.0307 AC: 1641 AN: 53410

Middle Eastern (MID) AF: 0.0241 AC: 139 AN: 5756

European-Non Finnish (NFE) AF: 0.0219 AC: 24349 AN: 1110968

Other (OTH) AF: 0.0207 AC: 1251 AN: 60296

GnomAD4 genome AF: 0.0173 AC: 2627 AN: 152044 Hom.: 40 Cov.: 31 AF XY: 0.0176 AC XY: 1305 AN XY: 74332

African (AFR) AF: 0.00516 AC: 214 AN: 41500

American (AMR) AF: 0.0183 AC: 279 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4820

European-Finnish (FIN) AF: 0.0318 AC: 337 AN: 10598

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1599 AN: 67920

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.0214 Hom.: 17

Bravo AF: 0.0159

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0217

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Aortic aneurysm, familial thoracic 8 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.0
DANN	Benign	0.68
PhyloP100		-4.1
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: rs55806342; hg19: chr10-52913020;