chr1-42733658-T-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_148960.3(CLDN19):c.*1428A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 152,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CLDN19
NM_148960.3 3_prime_UTR
NM_148960.3 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.19
Genes affected
CLDN19 (HGNC:2040): (claudin 19) The product of this gene belongs to the claudin family. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in this gene are the cause of hypomagnesemia renal with ocular involvement (HOMGO). HOMGO is a progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [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=-0.9).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (172/152268) while in subpopulation NFE AF= 0.00163 (111/68004). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4. There are 83 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CLDN19 | NM_148960.3 | c.*1428A>G | 3_prime_UTR_variant | 5/5 | ENST00000296387.6 | NP_683763.2 | ||
| CLDN19 | NM_001123395.2 | c.*2210A>G | 3_prime_UTR_variant | 4/4 | NP_001116867.1 | |||
| CLDN19 | NM_001185117.2 | c.*2104A>G | 3_prime_UTR_variant | 3/3 | NP_001172046.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CLDN19 | ENST00000296387.6 | c.*1428A>G | 3_prime_UTR_variant | 5/5 | 2 | NM_148960.3 | ENSP00000296387 | |||
| CLDN19 | ENST00000539749.5 | c.*2104A>G | 3_prime_UTR_variant | 3/3 | 2 | ENSP00000443229 |
Frequencies
GnomAD3 genomes 0.00113 AC: 172AN: 152150Hom.: 0 Cov.: 32
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 46Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 30
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GnomAD4 genome 0.00113 AC: 172AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83AN XY: 74464
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Renal hypomagnesemia 5 with ocular involvement Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at