rs1253995767
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006580.4(CLDN16):c.335_338dup(p.Lys113AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CLDN16
NM_006580.4 frameshift
NM_006580.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.813
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-190404877-C-CATTA is Pathogenic according to our data. Variant chr3-190404877-C-CATTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545703.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLDN16 | NM_006580.4 | c.335_338dup | p.Lys113AsnfsTer2 | frameshift_variant | 3/5 | ENST00000264734.3 | |
CLDN16 | NM_001378492.1 | c.335_338dup | p.Lys113AsnfsTer2 | frameshift_variant | 7/9 | ||
CLDN16 | NM_001378493.1 | c.335_338dup | p.Lys113AsnfsTer2 | frameshift_variant | 6/8 | ||
CLDN16 | XM_047447333.1 | c.335_338dup | p.Lys113AsnfsTer2 | frameshift_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLDN16 | ENST00000264734.3 | c.335_338dup | p.Lys113AsnfsTer2 | frameshift_variant | 3/5 | 1 | NM_006580.4 | P1 | |
CLDN16 | ENST00000456423.2 | c.115-5024_115-5021dup | intron_variant | 1 | |||||
CLDN16 | ENST00000468220.1 | n.527_530dup | non_coding_transcript_exon_variant | 5/5 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251482Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727228
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary hypomagnesemia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 29, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 19, 2022 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at