rs5705

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.627

Publications

30 publications found

Variant links:

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

REN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REN	NM_000537.4 link	c.204A>C	p.Thr68Thr	synonymous_variant	Exon 2 of 10	ENST00000272190.9	NP_000528.1	P00797-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REN	ENST00000272190.9 link	c.204A>C	p.Thr68Thr	synonymous_variant	Exon 2 of 10	1	NM_000537.4	ENSP00000272190.8		P00797-1
REN	ENST00000638118.1 link	c.90A>C	p.Thr30Thr	synonymous_variant	Exon 4 of 12	5		ENSP00000490307.1		A0A1B0GUZ2

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27252

AN:

151926

Hom.:

2915

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.128

AC XY:

92719

AN XY:

727174

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9373

18746

28118

37491

46864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4998

9996

14994

19992

24990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.180

AC:

27304

AN:

152044

Hom.:

2924

Cov.:

AF XY:

0.178

AC XY:

13224

AN XY:

74322

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8620

AN:

67972

Other (OTH)

AF:

0.160

AC:

336

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1114

2227

3341

4454

5568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.143

Hom.:

3405

Bravo

AF:

0.192

Asia WGS

AF:

0.134

AC:

468

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal tubular dysgenesis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial juvenile hyperuricemic nephropathy type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.2

(source)

DANN

Benign

0.23

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over