10-50991235-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3847 AD 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.-144C>A		5_prime_UTR	Exon 1 of 18	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.-144C>A		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

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

African (AFR) AF: 0.0382 AC: 736 AN: 19278

American (AMR) AF: 0.0112 AC: 182 AN: 16180

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 319 AN: 16312

East Asian (EAS) AF: 0.0483 AC: 1359 AN: 28132

South Asian (SAS) AF: 0.0138 AC: 779 AN: 56562

European-Finnish (FIN) AF: 0.0333 AC: 1413 AN: 42458

Middle Eastern (MID) AF: 0.0149 AC: 47 AN: 3164

European-Non Finnish (NFE) AF: 0.0184 AC: 15487 AN: 843024

Other (OTH) AF: 0.0197 AC: 884 AN: 44912

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

African (AFR) AF: 0.0327 AC: 1357 AN: 41522

American (AMR) AF: 0.0148 AC: 227 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.0401 AC: 206 AN: 5140

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4822

European-Finnish (FIN) AF: 0.0329 AC: 349 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1507 AN: 67982

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0252 Hom.: 55

Bravo AF: 0.0244

Asia WGS AF: 0.0250 AC: 88 AN: 3478

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	-0.75
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		1.1
PromoterAI		0.10	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs114234235; hg19: chr10-52750995;