10-50991235-C-A

Variant names:

• chr10-50991235-C-A
• rs114234235
• NM_001098512.3:c.-144C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001098512.3(PRKG1):​c.-144C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,222,170 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (61 hom., cov: 29)
  • Exomes 𝑓: 0.020 (401 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-50991235-C-A is Benign according to our data. Variant chr10-50991235-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 674736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0253 (3847/152148) while in subpopulation EAS AF= 0.0401 (206/5140). AF 95% confidence interval is 0.0356. There are 61 homozygotes in gnomad4. There are 1923 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_001098512.3	c.-144C>A		5_prime_UTR_variant	Exon 1 of 18		NP_001091982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000401604	c.-144C>A		5_prime_UTR_variant	Exon 1 of 18	5		ENSP00000384200.4

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3843 AN: 152032 Hom.: 60 Cov.: 29

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0398

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0198 AC: 21206 AN: 1070022 Hom.: 401 Cov.: 14 AF XY: 0.0198 AC XY: 10501 AN XY: 530074

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0483

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0253 AC: 3847 AN: 152148 Hom.: 61 Cov.: 29 AF XY: 0.0259 AC XY: 1923 AN XY: 74370

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0287 Hom.: 10

Bravo AF: 0.0244

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs114234235; hg19: chr10-52750995;