10-50991310-AGCCGCCGCCGCCGCCGCCGCCGCC-AGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr10-50991310-A-AGCCGCCGCCGCC
• rs79957958
• NM_001098512.3:c.-47_-36dupGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001098512.3(PRKG1):​c.-47_-36dupGCCGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (209 hom., cov: 0)
  • Exomes 𝑓: 0.043 (1210 hom.)
• Consequence: PRKG1 NM_001098512.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 10-50991310-A-AGCCGCCGCCGCC is Benign according to our data. Variant chr10-50991310-A-AGCCGCCGCCGCC is described in ClinVar as Benign. ClinVar VariationId is 1296422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.076 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.-47_-36dupGCCGCCGCCGCC		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.-47_-36dupGCCGCCGCCGCC		5_prime_UTR	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6419 AN: 143722 Hom.: 209 Cov.: 0

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.0179

Gnomad FIN AF: 0.0805

Gnomad MID AF: 0.0131

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0485

GnomAD4 exome AF: 0.0426 AC: 52975 AN: 1243004 Hom.: 1210 Cov.: 13 AF XY: 0.0421 AC XY: 25784 AN XY: 612848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00684 AC: 149 AN: 21772

American (AMR) AF: 0.0119 AC: 278 AN: 23452

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 613 AN: 20094

East Asian (EAS) AF: 0.0858 AC: 2407 AN: 28044

South Asian (SAS) AF: 0.00441 AC: 296 AN: 67162

European-Finnish (FIN) AF: 0.0553 AC: 2443 AN: 44140

Middle Eastern (MID) AF: 0.0177 AC: 73 AN: 4132

European-Non Finnish (NFE) AF: 0.0456 AC: 44883 AN: 983298

Other (OTH) AF: 0.0360 AC: 1833 AN: 50910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0446 AC: 6417 AN: 143820 Hom.: 209 Cov.: 0 AF XY: 0.0454 AC XY: 3168 AN XY: 69826

African (AFR) AF: 0.0129 AC: 509 AN: 39364

American (AMR) AF: 0.0407 AC: 576 AN: 14162

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 198 AN: 3366

East Asian (EAS) AF: 0.0830 AC: 364 AN: 4384

South Asian (SAS) AF: 0.0176 AC: 80 AN: 4534

European-Finnish (FIN) AF: 0.0805 AC: 780 AN: 9694

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.0561 AC: 3658 AN: 65184

Other (OTH) AF: 0.0479 AC: 95 AN: 1982

Alfa AF: 0.0365 Hom.: 279

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
PhyloP100		2.4
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs79957958; hg19: chr10-52751070;