rs104893721
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_006580.4(CLDN16):c.505G>A(p.Gly169Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,870 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 (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
CLDN16
NM_006580.4 missense
NM_006580.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.24
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a topological_domain Extracellular (size 32) in uniprot entity CLD16_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006580.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 3-190408436-G-A is Pathogenic according to our data. Variant chr3-190408436-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-190408436-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLDN16 | NM_006580.4 | c.505G>A | p.Gly169Arg | missense_variant | 4/5 | ENST00000264734.3 | NP_006571.2 | |
CLDN16 | NM_001378492.1 | c.505G>A | p.Gly169Arg | missense_variant | 8/9 | NP_001365421.1 | ||
CLDN16 | NM_001378493.1 | c.505G>A | p.Gly169Arg | missense_variant | 7/8 | NP_001365422.1 | ||
CLDN16 | XM_047447333.1 | c.505G>A | p.Gly169Arg | missense_variant | 6/7 | XP_047303289.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLDN16 | ENST00000264734.3 | c.505G>A | p.Gly169Arg | missense_variant | 4/5 | 1 | NM_006580.4 | ENSP00000264734 | P1 | |
CLDN16 | ENST00000456423.2 | c.115-1467G>A | intron_variant | 1 | ENSP00000414136 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251464Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
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GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727234
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GnomAD4 genome Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary hypomagnesemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2000 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 03, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CLDN16 function (PMID: 16234325). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 5926). This missense change has been observed in individuals with hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 10390358, 10878661, 11518780, 18003771, 25477417). This variant is present in population databases (rs104893721, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 239 of the CLDN16 protein (p.Gly239Arg). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0105);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at