chr10-52161958-A-G

Variant names:

• chr10-52161958-A-G
• rs75650199
• NM_006258.4:c.1071A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006258.4(PRKG1):​c.1071A>G​(p.Lys357Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,610,520 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: PRKG1 NM_006258.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.89
• 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, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-52161958-A-G is Benign according to our data. Variant chr10-52161958-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.89 with no splicing effect.
• BS2: High AC in GnomAd4 at 146 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.1071A>G	p.Lys357Lys	synonymous	Exon 9 of 18	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.1026A>G	p.Lys342Lys	synonymous	Exon 9 of 18	NP_001091982.1	Q13976-1
	PRKG1	NM_001374781.1		c.-139A>G		5_prime_UTR	Exon 5 of 14	NP_001361710.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.1071A>G	p.Lys357Lys	synonymous	Exon 9 of 18	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.1026A>G	p.Lys342Lys	synonymous	Exon 9 of 18	ENSP00000384200.4	Q13976-1
	PRKG1	ENST00000672084.1		c.222A>G	p.Lys74Lys	synonymous	Exon 3 of 11	ENSP00000499822.1	A0A5F9ZGW0

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 146 AN: 151928 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000838 AC: 209 AN: 249390 AF XY: 0.000905

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.000641

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000938

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.00166 AC: 2428 AN: 1458474 Hom.: 5 Cov.: 30 AF XY: 0.00167 AC XY: 1209 AN XY: 725582

African (AFR) AF: 0.000299 AC: 10 AN: 33394

American (AMR) AF: 0.000807 AC: 36 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39554

South Asian (SAS) AF: 0.00114 AC: 98 AN: 85932

European-Finnish (FIN) AF: 0.0000944 AC: 5 AN: 52944

Middle Eastern (MID) AF: 0.000960 AC: 5 AN: 5206

European-Non Finnish (NFE) AF: 0.00197 AC: 2191 AN: 1110520

Other (OTH) AF: 0.00136 AC: 82 AN: 60232

GnomAD4 genome AF: 0.000960 AC: 146 AN: 152046 Hom.: 1 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74318

African (AFR) AF: 0.000435 AC: 18 AN: 41368

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 67988

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.000975

EpiCase AF: 0.00207

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Aortic aneurysm, familial thoracic 8 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	PRKG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		2.9
Mutation Taster		=92/8	polymorphism

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: rs75650199; hg19: chr10-53921718;