rs387907324
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000782.5(CYP24A1):c.964G>A(p.Glu322Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,602,204 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_000782.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP24A1 | ENST00000216862.8 | c.964G>A | p.Glu322Lys | missense_variant | Exon 7 of 12 | 1 | NM_000782.5 | ENSP00000216862.3 | ||
CYP24A1 | ENST00000395955.7 | c.964G>A | p.Glu322Lys | missense_variant | Exon 7 of 11 | 1 | ENSP00000379285.3 | |||
CYP24A1 | ENST00000395954.3 | c.538G>A | p.Glu180Lys | missense_variant | Exon 5 of 10 | 1 | ENSP00000379284.3 | |||
CYP24A1 | ENST00000487593.1 | n.217G>A | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151890Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251490Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.0000200 AC: 29AN: 1450314Hom.: 0 Cov.: 26 AF XY: 0.0000221 AC XY: 16AN XY: 722424
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151890Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74164
ClinVar
Submissions by phenotype
Hypercalcemia, infantile, 1 Pathogenic:2
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not provided Pathogenic:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 322 of the CYP24A1 protein (p.Glu322Lys). This variant is present in population databases (rs387907324, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of CYP24A1-related conditions (PMID: 21675912, 28470390, 33099630, 34307984, 34662328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 29681). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP24A1 protein function. Experimental studies have shown that this missense change affects CYP24A1 function (PMID: 21675912). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at