chr10-50991696-G-C

Variant names:

• chr10-50991696-G-C
• rs555654395
• NM_001098512.3:c.266+52G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001098512.3(PRKG1):​c.266+52G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,224,034 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (15 hom.)
• Consequence: PRKG1 NM_001098512.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.113
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 10-50991696-G-C is Benign according to our data. Variant chr10-50991696-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1219572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 419 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098512.3. 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_001098512.3		c.266+52G>C		intron	N/A	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.266+52G>C		intron	N/A	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 419 AN: 150512 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000582

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000397

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00323 AC: 3467 AN: 1073414 Hom.: 15 AF XY: 0.00332 AC XY: 1704 AN XY: 512614

African (AFR) AF: 0.000582 AC: 12 AN: 20634

American (AMR) AF: 0.000611 AC: 4 AN: 6550

Ashkenazi Jewish (ASJ) AF: 0.000906 AC: 11 AN: 12142

East Asian (EAS) AF: 0.00 AC: 0 AN: 20574

South Asian (SAS) AF: 0.00222 AC: 63 AN: 28440

European-Finnish (FIN) AF: 0.0113 AC: 369 AN: 32742

Middle Eastern (MID) AF: 0.00256 AC: 7 AN: 2736

European-Non Finnish (NFE) AF: 0.00319 AC: 2903 AN: 908698

Other (OTH) AF: 0.00240 AC: 98 AN: 40898

GnomAD4 genome AF: 0.00278 AC: 419 AN: 150620 Hom.: 1 Cov.: 32 AF XY: 0.00318 AC XY: 234 AN XY: 73576

African (AFR) AF: 0.000581 AC: 24 AN: 41324

American (AMR) AF: 0.000397 AC: 6 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.0127 AC: 125 AN: 9860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00367 AC: 248 AN: 67618

Other (OTH) AF: 0.00191 AC: 4 AN: 2094

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00179

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.5
DANN	Benign	0.89
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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: rs555654395; hg19: chr10-52751456;