16-1212118-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_021098.3(CACNA1H):c.4739G>C(p.Arg1580Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,607,992 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 Uncertain significance (★★).
Frequency
Consequence
NM_021098.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.4739G>C | p.Arg1580Pro | missense_variant | Exon 25 of 35 | 1 | NM_021098.3 | ENSP00000334198.7 | ||
CACNA1H | ENST00000565831.6 | c.4739G>C | p.Arg1580Pro | missense_variant | Exon 24 of 33 | 1 | ENSP00000455840.1 | |||
CACNA1H | ENST00000638323.1 | c.4700G>C | p.Arg1567Pro | missense_variant | Exon 25 of 35 | 5 | ENSP00000492267.1 | |||
CACNA1H | ENST00000569107.5 | c.962G>C | p.Arg321Pro | missense_variant | Exon 8 of 17 | 1 | ENSP00000454990.2 | |||
CACNA1H | ENST00000564231.5 | c.962G>C | p.Arg321Pro | missense_variant | Exon 8 of 18 | 1 | ENSP00000457555.2 | |||
CACNA1H | ENST00000562079.5 | c.962G>C | p.Arg321Pro | missense_variant | Exon 8 of 17 | 1 | ENSP00000454581.2 | |||
CACNA1H | ENST00000639478.1 | n.4677G>C | non_coding_transcript_exon_variant | Exon 25 of 35 | 5 | ENSP00000491945.1 | ||||
CACNA1H | ENST00000640028.1 | n.*2590G>C | non_coding_transcript_exon_variant | Exon 25 of 35 | 5 | ENSP00000491488.1 | ||||
CACNA1H | ENST00000640028.1 | n.*2590G>C | 3_prime_UTR_variant | Exon 25 of 35 | 5 | ENSP00000491488.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000821 AC: 2AN: 243626Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132944
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455818Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2AN XY: 724416
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.4739G>C (p.R1580P) alteration is located in exon 25 (coding exon 24) of the CACNA1H gene. This alteration results from a G to C substitution at nucleotide position 4739, causing the arginine (R) at amino acid position 1580 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1580 of the CACNA1H protein (p.Arg1580Pro). This variant is present in population databases (rs200627008, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 2295465). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function with a negative predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at