3-190388114-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001378492.1(CLDN16):c.-93-123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,560 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 1 hom. )
Consequence
CLDN16
NM_001378492.1 intron
NM_001378492.1 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.47
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000151 (23/152224) while in subpopulation EAS AF= 0.00445 (23/5164). AF 95% confidence interval is 0.00304. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLDN16 | NM_001378492.1 | c.-93-123C>T | intron_variant | ||||
CLDN16 | NM_001378493.1 | c.-93-123C>T | intron_variant | ||||
CLDN16 | XM_047447333.1 | c.-93-123C>T | intron_variant | ||||
CLDN16 | NM_006580.4 | upstream_gene_variant | ENST00000264734.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLDN16 | ENST00000468220.1 | n.306+13511C>T | intron_variant, non_coding_transcript_variant | 4 | |||||
CLDN16 | ENST00000264734.3 | upstream_gene_variant | 1 | NM_006580.4 | P1 | ||||
CLDN16 | ENST00000456423.2 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000252 AC: 63AN: 250290Hom.: 0 AF XY: 0.000237 AC XY: 32AN XY: 135282
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461336Hom.: 1 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 726982
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74414
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary hypomagnesemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at