rs376174664

Variant names:

• chr10-52293786-T-G
• rs376174664
• NM_006258.4:c.1963-16T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006258.4(PRKG1):​c.1963-16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,598,792 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.148
• 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-AS1 (HGNC:45029): (PRKG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-52293786-T-G is Benign according to our data. Variant chr10-52293786-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 77 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006258.4. 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_006258.4	MANE Select	c.1963-16T>G		intron	N/A	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.1918-16T>G		intron	N/A	NP_001091982.1	Q13976-1
	PRKG1	NM_001374781.1		c.754-16T>G		intron	N/A	NP_001361710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.1963-16T>G		intron	N/A	ENSP00000363092.5	Q13976-2
	PRKG1-AS1	ENST00000426785.2	TSL:1	n.169+129A>C		intron	N/A
	PRKG1	ENST00000401604.8	TSL:5	c.1918-16T>G		intron	N/A	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000401 AC: 98 AN: 244148 AF XY: 0.000440

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000805 AC: 1164 AN: 1446706 Hom.: 2 Cov.: 29 AF XY: 0.000825 AC XY: 594 AN XY: 720092

African (AFR) AF: 0.000213 AC: 7 AN: 32830

American (AMR) AF: 0.0000232 AC: 1 AN: 43158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84402

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00102 AC: 1129 AN: 1102096

Other (OTH) AF: 0.000418 AC: 25 AN: 59794

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 40 AN XY: 74290

African (AFR) AF: 0.000217 AC: 9 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000423

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Aortic aneurysm, familial thoracic 8 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.22
DANN	Benign	0.70
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs376174664; hg19: chr10-54053546;