chr3-190388285-G-C

Variant names:

Variant summary

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

The NM_006580.4(CLDN16):c.-45G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,798 control chromosomes in the GnomAD database, including 41,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3026 hom., cov: 32)

Exomes 𝑓: 0.22 ( 38108 hom. )

Consequence

CLDN16
NM_006580.4 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0520

Publications

14 publications found

Variant links:

Genes affected

CLDN16 (HGNC:2037): (claudin 16) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

CLDN16 Gene-Disease associations (from GenCC):

renal hypomagnesemia 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

CLDN16 links:

ENSG00000297357 (HGNC:):

ENSG00000297357 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 (MetaRNN=0.0047626793).

BP6

Variant 3-190388285-G-C is Benign according to our data. Variant chr3-190388285-G-C is described in ClinVar as Benign. ClinVar VariationId is 344445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_006580.4 link	c.-45G>C	5_prime_UTR_variant	Exon 1 of 5	ENST00000264734.3	NP_006571.2	Q9Y5I7
CLDN16	NM_001378492.1 link	c.-45G>C	5_prime_UTR_variant	Exon 5 of 9		NP_001365421.1
CLDN16	NM_001378493.1 link	c.-45G>C	5_prime_UTR_variant	Exon 4 of 8		NP_001365422.1
CLDN16	XM_047447333.1 link	c.-45G>C	5_prime_UTR_variant	Exon 3 of 7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN16	ENST00000264734.3 link	c.-45G>C	5_prime_UTR_variant	Exon 1 of 5	1	NM_006580.4	ENSP00000264734.3	Q9Y5I7
CLDN16	ENST00000456423.2 link	c.-45G>C	5_prime_UTR_variant	Exon 1 of 2	1		ENSP00000414136.2	F6SGM4
ENSG00000297357	ENST00000747317.1 link	n.266C>G	non_coding_transcript_exon_variant	Exon 1 of 2
CLDN16	ENST00000468220.1 link	n.306+13682G>C	intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28239

AN:

151932

Hom.:

3027

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0905

Gnomad AMI

AF:

0.183

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.0263

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.212

GnomAD2 exomes

AF:

0.193

AC:

48454

AN:

250974

AF XY:

0.200

show subpopulations

Gnomad AFR exome

AF:

0.0857

Gnomad AMR exome

AF:

0.110

Gnomad ASJ exome

AF:

0.276

Gnomad EAS exome

AF:

0.0199

Gnomad FIN exome

AF:

0.254

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.222

AC:

324468

AN:

1461748

Hom.:

38108

Cov.:

AF XY:

0.222

AC XY:

161310

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0869

AC:

2908

AN:

33478

American (AMR)

AF:

0.113

AC:

5066

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

7142

AN:

26134

East Asian (EAS)

AF:

0.0291

AC:

1155

AN:

39694

South Asian (SAS)

AF:

0.172

AC:

14802

AN:

86256

European-Finnish (FIN)

AF:

0.253

AC:

13494

AN:

53412

Middle Eastern (MID)

AF:

0.270

AC:

1560

AN:

5768

European-Non Finnish (NFE)

AF:

0.239

AC:

265307

AN:

1111894

Other (OTH)

AF:

0.216

AC:

13034

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

15534

31068

46603

62137

77671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8778

17556

26334

35112

43890

<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:

0.186

AC:

28251

AN:

152050

Hom.:

3026

Cov.:

AF XY:

0.186

AC XY:

13794

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0906

AC:

3763

AN:

41514

American (AMR)

AF:

0.174

AC:

2667

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

933

AN:

3468

East Asian (EAS)

AF:

0.0265

AC:

137

AN:

5168

South Asian (SAS)

AF:

0.168

AC:

809

AN:

4822

European-Finnish (FIN)

AF:

0.257

AC:

2708

AN:

10552

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.244

AC:

16545

AN:

67928

Other (OTH)

AF:

0.208

AC:

439

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1139

2278

3418

4557

5696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.230

Hom.:

3157

Bravo

AF:

0.172

ExAC

AF:

0.194

AC:

23607

Asia WGS

AF:

0.0890

AC:

312

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

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

- -

Primary hypomagnesemia

Benign:2

Jan 13, 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala56Pro in exon 1 of CLDN16: This variant is not expected to have clinical si gnificance because it has been identified in 25.09% (16723/66656) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs3214506). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

2.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.55

N;.

PhyloP100

-0.052

PrimateAI

Benign

0.26

PROVEAN

Benign

0.080

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.13

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.16

MPC

0.14

ClinPred

0.00072

GERP RS

-3.9

PromoterAI

0.063

Neutral

(source)

Varity_R

0.070

gMVP

0.12

Mutation Taster

=98/2

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