chr10-50990905-C-T

Variant names:

• chr10-50990905-C-T
• rs2248908
• NM_001098512.3:c.-474C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001098512.3(PRKG1):​c.-474C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.90 (56051 hom., cov: 17)
  • Exomes 𝑓: 0.81 (357 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.386
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-50990905-C-T is Benign according to our data. Variant chr10-50990905-C-T is described in ClinVar as Benign. ClinVar VariationId is 683714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

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.-474C>T		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.-474C>T		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.898 AC: 124584 AN: 138804 Hom.: 55999 Cov.: 17

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.847

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.811 AC: 863 AN: 1064 Hom.: 357 Cov.: 0 AF XY: 0.819 AC XY: 480 AN XY: 586

African (AFR) AF: 1.00 AC: 6 AN: 6

American (AMR) AF: 0.800 AC: 16 AN: 20

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 9 AN: 12

East Asian (EAS) AF: 1.00 AC: 6 AN: 6

South Asian (SAS) AF: 0.789 AC: 60 AN: 76

European-Finnish (FIN) AF: 0.708 AC: 17 AN: 24

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.818 AC: 684 AN: 836

Other (OTH) AF: 0.787 AC: 63 AN: 80

GnomAD4 genome AF: 0.898 AC: 124688 AN: 138912 Hom.: 56051 Cov.: 17 AF XY: 0.896 AC XY: 59829 AN XY: 66756

African (AFR) AF: 0.952 AC: 34738 AN: 36482

American (AMR) AF: 0.886 AC: 12190 AN: 13758

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 2992 AN: 3386

East Asian (EAS) AF: 0.944 AC: 4355 AN: 4614

South Asian (SAS) AF: 0.853 AC: 3276 AN: 3840

European-Finnish (FIN) AF: 0.858 AC: 7336 AN: 8550

Middle Eastern (MID) AF: 0.856 AC: 238 AN: 278

European-Non Finnish (NFE) AF: 0.876 AC: 57130 AN: 65248

Other (OTH) AF: 0.884 AC: 1664 AN: 1882

Alfa AF: 0.887 Hom.: 7273

Bravo AF: 0.903

Asia WGS AF: 0.909 AC: 3163 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	11
DANN	Benign	0.67
PhyloP100		0.39
PromoterAI		0.011	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2248908; hg19: chr10-52750665;