rs118203979
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_148960.3(CLDN19):c.59G>A(p.Gly20Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,577,704 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 Likely pathogenic (★★).
Frequency
Consequence
NM_148960.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLDN19 | NM_148960.3 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 5 | ENST00000296387.6 | NP_683763.2 | |
CLDN19 | NM_001185117.2 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 3 | NP_001172046.1 | ||
CLDN19 | NM_001123395.2 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 4 | NP_001116867.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLDN19 | ENST00000296387.6 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 5 | 2 | NM_148960.3 | ENSP00000296387.1 | ||
CLDN19 | ENST00000372539.3 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 4 | 1 | ENSP00000361617.3 | |||
CLDN19 | ENST00000539749.5 | c.59G>A | p.Gly20Asp | missense_variant | Exon 1 of 3 | 2 | ENSP00000443229.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000898 AC: 17AN: 189278Hom.: 0 AF XY: 0.0000885 AC XY: 9AN XY: 101742
GnomAD4 exome AF: 0.0000224 AC: 32AN: 1425394Hom.: 0 Cov.: 31 AF XY: 0.0000241 AC XY: 17AN XY: 705954
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74484
ClinVar
Submissions by phenotype
Renal hypomagnesemia 5 with ocular involvement Pathogenic:5
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not provided Pathogenic:2
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 20 of the CLDN19 protein (p.Gly20Asp). 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 individuals with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (PMID: 17033971, 23301036, 25366522, 25410674, 27530400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLDN19 function (PMID: 17033971, 18188451). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a damaging effect on protein trafficking and/or assembly, impairing its function during renal tubular and retinal epithelial development (Konrad et al., 2006; Wang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18188451, Xu2017[abstract], 25366522, 30937396, 25317625, 17033971, 27530400, 22422540, 34425238, 31694170, 33532864, 25410674) -
CLDN19-related disorder Pathogenic:1
The CLDN19 c.59G>A variant is predicted to result in the amino acid substitution p.Gly20Asp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with familial hypomagnesemia, hypercalciuria, and nephrocalcinosis with ocular abnormalities (see for example, Figure 2, Konrad et al. 2006. PubMed ID: 17033971; Almeida et al. 2014. PubMed ID: 25317625; Table 1, Martin-Nuñez et al. 2014. PubMed ID: 25410674). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD. Functional studies suggest this variant impairs protein function (Figure 2, Hou et al. 2008. PubMed ID: 18188451; Figure 2, Wang et al. 2019. PubMed ID: 30937396). This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at