rs746515147
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000388.4(CASR):c.1287C>A(p.His429Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H429R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.1287C>A | p.His429Gln | missense_variant | 4/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.1287C>A | p.His429Gln | missense_variant | 4/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.1287C>A | p.His429Gln | missense_variant | 4/7 | 1 | |||
CASR | ENST00000638421.1 | c.1287C>A | p.His429Gln | missense_variant | 4/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.1287C>A | p.His429Gln | missense_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251228Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135768
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461618Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727134
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74468
ClinVar
Submissions by phenotype
Nephrolithiasis/nephrocalcinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2023 | The p.H429Q variant (also known as c.1287C>A), located in coding exon 3 of the CASR gene, results from a C to A substitution at nucleotide position 1287. The histidine at codon 429 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2023 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 429 of the CASR protein (p.His429Gln). This variant is present in population databases (rs746515147, gnomAD 0.02%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 463895). This missense change has been observed in individual(s) with hypoparathyroidism (PMID: 31433868). - |
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 27, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at