rs5705

Variant names:

• chr1-204162058-T-G
• rs5705
• NM_000537.4:c.204A>C

Variant summary

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

The NM_000537.4(REN):​c.204A>C​(p.Thr68Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,772 control chromosomes in the GnomAD database, including 16,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2924 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13126 hom.)
• Consequence: REN NM_000537.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.627
• Publications: 30 publications found

Genes affected

REN (HGNC:9958): (renin) This gene encodes renin, an aspartic protease that is secreted by the kidneys. Renin is a part of the renin-angiotensin-aldosterone system involved in regulation of blood pressure, and electrolyte balance. This enzyme catalyzes the first step in the activation pathway of angiotensinogen by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by angiotensin I converting enzyme. This cascade can result in aldosterone release, narrowing of blood vessels, and increase in blood pressure as angiotension II is a vasoconstrictive peptide. Transcript variants that encode different protein isoforms and that arise from alternative splicing and the use of alternative promoters have been described, but their full-length nature has not been determined. Mutations in this gene have been shown to cause hyperuricemic nephropathy familial juvenile 2, familial hyperproreninemia, and renal tubular dysgenesis. [provided by RefSeq, May 2020]

REN Gene-Disease associations (from GenCC):

• familial juvenile hyperuricemic nephropathy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-204162058-T-G is Benign according to our data. Variant chr1-204162058-T-G is described in ClinVar as Benign. ClinVar VariationId is 256379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000537.4. 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
	REN	NM_000537.4	MANE Select	c.204A>C	p.Thr68Thr	synonymous	Exon 2 of 10	NP_000528.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REN	ENST00000272190.9	TSL:1 MANE Select	c.204A>C	p.Thr68Thr	synonymous	Exon 2 of 10	ENSP00000272190.8
	REN	ENST00000851325.1		c.204A>C	p.Thr68Thr	synonymous	Exon 2 of 9	ENSP00000521384.1
	REN	ENST00000638118.1	TSL:5	c.90A>C	p.Thr30Thr	synonymous	Exon 4 of 12	ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27252 AN: 151926 Hom.: 2915 Cov.: 31

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.141 AC: 35385 AN: 251010 AF XY: 0.136

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0882

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.128 AC: 187069 AN: 1461728 Hom.: 13126 Cov.: 32 AF XY: 0.128 AC XY: 92719 AN XY: 727174

African (AFR) AF: 0.324 AC: 10841 AN: 33476

American (AMR) AF: 0.177 AC: 7918 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4127 AN: 26136

East Asian (EAS) AF: 0.0831 AC: 3298 AN: 39696

South Asian (SAS) AF: 0.114 AC: 9801 AN: 86242

European-Finnish (FIN) AF: 0.111 AC: 5912 AN: 53416

Middle Eastern (MID) AF: 0.184 AC: 1061 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135642 AN: 1111920

Other (OTH) AF: 0.140 AC: 8469 AN: 60392

GnomAD4 genome AF: 0.180 AC: 27304 AN: 152044 Hom.: 2924 Cov.: 31 AF XY: 0.178 AC XY: 13224 AN XY: 74322

African (AFR) AF: 0.312 AC: 12931 AN: 41444

American (AMR) AF: 0.171 AC: 2607 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3470

East Asian (EAS) AF: 0.0913 AC: 471 AN: 5160

South Asian (SAS) AF: 0.108 AC: 522 AN: 4816

European-Finnish (FIN) AF: 0.102 AC: 1084 AN: 10592

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8620 AN: 67972

Other (OTH) AF: 0.160 AC: 336 AN: 2106

Alfa AF: 0.143 Hom.: 3405

Bravo AF: 0.192

Asia WGS AF: 0.134 AC: 468 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial juvenile hyperuricemic nephropathy type 2 (1)
-	-	1	not specified (1)
-	-	1	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.23
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: rs5705; hg19: chr1-204131186; COSMIC: COSV65817452;