rs104893729

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_006580.4(CLDN16):c.243G>T(p.Leu81Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L81W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CLDN16
NM_006580.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.58

Publications

22 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006580.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-190404786-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5935.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.076836 (below the threshold of 3.09). Trascript score misZ: 0.28069 (below the threshold of 3.09). GenCC associations: The gene is linked to renal hypomagnesemia 3.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-190404787-G-T is Pathogenic according to our data. Variant chr3-190404787-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_006580.4 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 3 of 5	ENST00000264734.3	NP_006571.2	Q9Y5I7
CLDN16	NM_001378492.1 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 7 of 9		NP_001365421.1
CLDN16	NM_001378493.1 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 6 of 8		NP_001365422.1
CLDN16	XM_047447333.1 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 5 of 7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN16	ENST00000264734.3 link	c.243G>T	p.Leu81Phe	missense_variant	Exon 3 of 5	1	NM_006580.4	ENSP00000264734.3	Q9Y5I7
CLDN16	ENST00000456423.2 link	c.115-5116G>T		intron_variant	Intron 1 of 1	1		ENSP00000414136.2	F6SGM4
CLDN16	ENST00000468220.1 link	n.435G>T		non_coding_transcript_exon_variant	Exon 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000716

AC:

AN:

251492

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

1112004

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hypomagnesemia

Pathogenic:4

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 26, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variant, NM_006580.3(CLDN16):c.453G>T, has been identified in exon 3 of 5 of the CLDN16 gene. The variant is predicted to result in a minor amino acid change from leucine to phenylalanine at position 151 of the protein (NP_006571.1(CLDN16):p.(Leu151Phe)). The leucine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the Claudin superfamily domain. In silico predictions for this variant are consistently pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD database at a frequency of 0.007% (19 heterozygotes; 0 homozygotes). More than 33 homozygous CLDN16 p.(Leu151Phe) cases with Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) have been reported to date (ClinVar, OMIM, Weber, S. et al. (2000), Weber, S. et al. (2001), Konrad, M. et al. (2008), Li, H. et al. (2017)). The mutation is likely due to a founder effect in the European population (Weber, S. et al. (2001)). The homozygous variant has been reported to segregate with disease in 25 unrelated non-consanguinous families (Konrad, M. et al. (2008)). In addition, functional assays have shown >40% residual function of CLDN16 in cells expressing this variant, which corresponded with a later disease onset and slower progression of renal failure, compared to complete loss of function variants (Konrad, M. et al. (2008)). Alternate changes at residue 151 to tryptophan and proline have also been reported as pathogenic (ClinVar, Weber, S. et al. (2000), Konrad, M. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Sep 14, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of the available literature, the CLDN16 c.453G>T (p.Leu151Phe) missense variant has been identified in at least 28 individuals from more than 18 unrelated families with primary hypomagnesemia with hypercalciuria and nephrocalcinosis, including in a homozygous state in at least 18 individuals and in a compound heterozygous state in at least 10 individuals (Weber et al. 2000; Peco-AntiÄ‡ et al. 2010; Sikora et al. 2015). The variant was further identified in a heterozygous state in eight unaffected carrier parents (Weber et al. 2000). Two heterozygotes from one family had hypercalciuria but not primary hypomagnesemia (Tasic et al. 2005). The p.Leu151Phe variant was absent from 150 controls (Weber et al. 2000; Sikora et al. 2015) but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Genome Aggregation Database. Extended haplotype analysis suggests the p.Leu151Phe variant is likely a founder variant among patients originating from Germany or eastern European countries (Weber et al. 2000; Weber et al. 2001). Functional studies demonstrated that in transfected LLC-PK1 cells, the p.Leu151Phe variant led to partial function of the paracellin-1 protein compared to wild type (Hou et al. 2005). Based on the collective evidence, the p.Leu151Phe variant is classified as pathogenic for primary hypomagnesemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 151 of the CLDN16 protein (p.Leu151Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 10878661). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5934). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLDN16 protein function. 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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.8

PhyloP100

3.6

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.87

MutPred

0.92

Gain of catalytic residue at L151 (P = 0.0078);

MVP

0.96

MPC

0.54

ClinPred

0.85

GERP RS

4.0

Varity_R

0.51

gMVP

0.64

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.67

Position offset: 14

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over