chr10-51299646-T-C

Variant names:

• chr10-51299646-T-C
• rs2043556
• NM_006258.4:c.478+146316T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006258.4(PRKG1):​c.478+146316T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 461,234 control chromosomes in the GnomAD database, including 14,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4677 hom., cov: 32)
  • Exomes 𝑓: 0.24 (10002 hom.)
• Consequence: PRKG1 NM_006258.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.634
• Publications: 83 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]

MIR605 (HGNC:32861): (microRNA 605) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 10-51299646-T-C is Benign according to our data. Variant chr10-51299646-T-C is described in ClinVar as Benign. ClinVar VariationId is 1232610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKG1	NM_006258.4	c.478+146316T>C		intron_variant	Intron 2 of 17	ENST00000373980.11	NP_006249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKG1	ENST00000373980.11	c.478+146316T>C		intron_variant	Intron 2 of 17	1	NM_006258.4	ENSP00000363092.5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37279 AN: 151836 Hom.: 4669 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.254 AC: 37396 AN: 147162 AF XY: 0.250

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.246

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.243 AC: 75193 AN: 309280 Hom.: 10002 Cov.: 0 AF XY: 0.243 AC XY: 42832 AN XY: 175926

African (AFR) AF: 0.233 AC: 1854 AN: 7968

American (AMR) AF: 0.432 AC: 10928 AN: 25282

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 2602 AN: 10876

East Asian (EAS) AF: 0.258 AC: 2230 AN: 8652

South Asian (SAS) AF: 0.249 AC: 14774 AN: 59260

European-Finnish (FIN) AF: 0.238 AC: 5466 AN: 22988

Middle Eastern (MID) AF: 0.251 AC: 687 AN: 2738

European-Non Finnish (NFE) AF: 0.212 AC: 33407 AN: 157426

Other (OTH) AF: 0.230 AC: 3245 AN: 14090

GnomAD4 genome AF: 0.246 AC: 37323 AN: 151954 Hom.: 4677 Cov.: 32 AF XY: 0.249 AC XY: 18465 AN XY: 74246

African (AFR) AF: 0.244 AC: 10107 AN: 41476

American (AMR) AF: 0.371 AC: 5671 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 879 AN: 3462

East Asian (EAS) AF: 0.271 AC: 1394 AN: 5140

South Asian (SAS) AF: 0.242 AC: 1168 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2593 AN: 10562

Middle Eastern (MID) AF: 0.210 AC: 61 AN: 290

European-Non Finnish (NFE) AF: 0.217 AC: 14704 AN: 67914

Other (OTH) AF: 0.265 AC: 558 AN: 2106

Alfa AF: 0.226 Hom.: 7383

Bravo AF: 0.256

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25683625)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-0.63
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: rs2043556; hg19: chr10-53059406; COSMIC: COSV64781969; COSMIC: COSV64781969;