4-81110483-T-TTACGCTCTTAAAGTATATACACTTTATCACTAGTTAGGTTATTTTTGCATTTCTCTGAAGAGGTG

Position:

• chr4-81110483-T-TTACGCTCTTAAAGTATATACACTTTATCACTAGTTAGGTTATTTTTGCATTTCTCTGAAGAGGTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006259.3(PRKG2):​c.1904_1905insCACCTCTTCAGAGAAATGCAAAAATAACCTAACTAGTGATAAAGTGTATATACTTTAAGAGCGTA​(p.Leu636ThrfsTer19) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKG2 NM_006259.3 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97

Genes affected

PRKG2 (HGNC:9416): (protein kinase cGMP-dependent 2) This gene encodes a protein that belongs to the serine/threonine protein kinase family of proteins. The encoded protein binds to and inhibits the activation of several receptor tyrosine kinases. The membrane-bound protein is a regulator of intestinal secretion, bone growth and renin secretion. Alternate splicing results in multiple transcript variants encoding distinct isoforms whose regulatory N-termini differ in length but whose C-terminal catalytic domains are identical. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-81110483-T-TTACGCTCTTAAAGTATATACACTTTATCACTAGTTAGGTTATTTTTGCATTTCTCTGAAGAGGTG is Pathogenic according to our data. Variant chr4-81110483-T-TTACGCTCTTAAAGTATATACACTTTATCACTAGTTAGGTTATTTTTGCATTTCTCTGAAGAGGTG is described in ClinVar as [Pathogenic]. Clinvar id is 2164608.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKG2	NM_006259.3	c.1904_1905insCACCTCTTCAGAGAAATGCAAAAATAACCTAACTAGTGATAAAGTGTATATACTTTAAGAGCGTA	p.Leu636ThrfsTer19	stop_gained, frameshift_variant	15/19	ENST00000264399.6	NP_006250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKG2	ENST00000264399.6	c.1904_1905insCACCTCTTCAGAGAAATGCAAAAATAACCTAACTAGTGATAAAGTGTATATACTTTAAGAGCGTA	p.Leu636ThrfsTer19	stop_gained, frameshift_variant	15/19	5	NM_006259.3	ENSP00000264399	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

This sequence change creates a premature translational stop signal (p.Leu636Thrfs*19) in the PRKG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRKG2 are known to be pathogenic (PMID: 19149413, 33106379). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRKG2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-82031637;