NM_001098512.3:c.-75C>A

Variant names:

• chr10-50991304-C-A
• rs559862615
• NM_001098512.3:c.-75C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001098512.3(PRKG1):​c.-75C>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 0.000353 in 1,426,278 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.886
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-50991304-C-A is Benign according to our data. Variant chr10-50991304-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1204833.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 304 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.-75C>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.-75C>A		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 304 AN: 110942 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000182

Gnomad OTH AF: 0.00211

GnomAD4 exome AF: 0.000152 AC: 200 AN: 1315216 Hom.: 2 Cov.: 27 AF XY: 0.000127 AC XY: 82 AN XY: 647554

African (AFR) AF: 0.00614 AC: 157 AN: 25560

American (AMR) AF: 0.000800 AC: 20 AN: 24986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21136

East Asian (EAS) AF: 0.00 AC: 0 AN: 31230

South Asian (SAS) AF: 0.00 AC: 0 AN: 70110

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 45986

Middle Eastern (MID) AF: 0.000228 AC: 1 AN: 4378

European-Non Finnish (NFE) AF: 0.00000482 AC: 5 AN: 1037740

Other (OTH) AF: 0.000296 AC: 16 AN: 54090

GnomAD4 genome AF: 0.00274 AC: 304 AN: 111062 Hom.: 1 Cov.: 29 AF XY: 0.00267 AC XY: 142 AN XY: 53206

African (AFR) AF: 0.0104 AC: 281 AN: 27124

American (AMR) AF: 0.00190 AC: 19 AN: 9996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2908

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 3240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.0000182 AC: 1 AN: 54934

Other (OTH) AF: 0.00208 AC: 3 AN: 1444

Alfa AF: 0.0000695 Hom.: 0

Bravo AF: 0.00202

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.2
DANN	Benign	0.89
PhyloP100		-0.89
PromoterAI		-0.099	Neutral

Splicing

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

Other links and lift over

dbSNP: rs559862615; hg19: chr10-52751064;