NM_006258.4:c.319G>C

Variant names:

• chr10-51153171-G-C
• rs751916382
• NM_006258.4:c.319G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006258.4(PRKG1):​c.319G>C​(p.Asp107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D107N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PRKG1 NM_006258.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.28
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30323997).
• BS2: High AC in GnomAdExome4 at 14 AD 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.319G>C	p.Asp107His	missense	Exon 2 of 18	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.274G>C	p.Asp92His	missense	Exon 2 of 18	NP_001091982.1	Q13976-1
	PRKG1	NM_001374782.1		c.319G>C	p.Asp107His	missense	Exon 2 of 7	NP_001361711.1	B1ALS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.319G>C	p.Asp107His	missense	Exon 2 of 18	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.274G>C	p.Asp92His	missense	Exon 2 of 18	ENSP00000384200.4	Q13976-1
	PRKG1	ENST00000645324.1		c.319G>C	p.Asp107His	missense	Exon 2 of 8	ENSP00000494124.1	A0A2R8Y507

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250072 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459276 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 725964

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110318

Other (OTH) AF: 0.0000498 AC: 3 AN: 60236

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Aortic aneurysm, familial thoracic 8 (2)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)
-	1	-	PRKG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0096	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.90	L
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.15	T
Sift4G	Benign	0.096	T
Polyphen		0.24	B
Vest4		0.36
MutPred		0.27		Gain of methylation at K91 (P = 0.0515)
MVP		0.63
MPC		0.75
ClinPred		0.29	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.66
Mutation Taster		=42/58	disease causing

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: rs751916382; hg19: chr10-52912931;