chr10-51931039-G-C

Variant names:

• chr10-51931039-G-C
• rs7082609
• NM_006258.4:c.762+23469G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006258.4(PRKG1):​c.762+23469G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 151,984 control chromosomes in the GnomAD database, including 29,560 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (29560 hom., cov: 31)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.137
• 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 Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.762+23469G>C		intron_variant	Intron 5 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.762+23469G>C		intron_variant	Intron 5 of 17	1	NM_006258.4	ENSP00000363092.5
PRKG1	ENST00000401604.8	c.717+23469G>C		intron_variant	Intron 5 of 17	5		ENSP00000384200.4
PRKG1	ENST00000645324.1	c.762+23469G>C		intron_variant	Intron 5 of 7			ENSP00000494124.1
PRKG1	ENST00000373976.9	c.762+23469G>C		intron_variant	Intron 5 of 6	3		ENSP00000363087.4

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92170 AN: 151866 Hom.: 29512 Cov.: 31

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.607

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.607 AC: 92268 AN: 151984 Hom.: 29560 Cov.: 31 AF XY: 0.607 AC XY: 45078 AN XY: 74256

African (AFR) AF: 0.828 AC: 34373 AN: 41504

American (AMR) AF: 0.535 AC: 8157 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1862 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2637 AN: 5144

South Asian (SAS) AF: 0.488 AC: 2347 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 5999 AN: 10536

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35211 AN: 67950

Other (OTH) AF: 0.600 AC: 1265 AN: 2108

Alfa AF: 0.568 Hom.: 3166

Bravo AF: 0.616

Asia WGS AF: 0.483 AC: 1682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7082609; hg19: chr10-53690799;