10-51074316-C-G

Position:

• chr10-51074316-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000645324.1(PRKG1):​c.-275C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 536,514 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (13 hom.)
• Consequence: PRKG1 ENST00000645324.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.205

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-51074316-C-G is Benign according to our data. Variant chr10-51074316-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1216927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKG1	NM_001098512.3	c.267-78848C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKG1	ENST00000645324.1	c.-275C>G		5_prime_UTR_variant	1/8
PRKG1	ENST00000401604.8	c.267-78848C>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1128 AN: 152036 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00741 AC: 2850 AN: 384362 Hom.: 13 Cov.: 7 AF XY: 0.00706 AC XY: 1354 AN XY: 191702

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.00285

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000616

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.00780

Gnomad4 OTH exome AF: 0.00615

GnomAD4 genome AF: 0.00741 AC: 1128 AN: 152152 Hom.: 7 Cov.: 32 AF XY: 0.00788 AC XY: 586 AN XY: 74374

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.00943

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00389 Hom.: 0

Bravo AF: 0.00610

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs541141424; hg19: chr10-52834076;