16-1208189-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_021098.3(CACNA1H):c.3331G>C(p.Gly1111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,550,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.
Frequency
Consequence
NM_021098.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.3331G>C | p.Gly1111Arg | missense_variant | Exon 16 of 35 | 1 | NM_021098.3 | ENSP00000334198.7 | ||
CACNA1H | ENST00000565831.6 | c.3331G>C | p.Gly1111Arg | missense_variant | Exon 15 of 33 | 1 | ENSP00000455840.1 | |||
CACNA1H | ENST00000638323.1 | c.3292G>C | p.Gly1098Arg | missense_variant | Exon 16 of 35 | 5 | ENSP00000492267.1 | |||
CACNA1H | ENST00000639478.1 | n.3331G>C | non_coding_transcript_exon_variant | Exon 16 of 35 | 5 | ENSP00000491945.1 | ||||
CACNA1H | ENST00000640028.1 | n.*1244G>C | non_coding_transcript_exon_variant | Exon 16 of 35 | 5 | ENSP00000491488.1 | ||||
CACNA1H | ENST00000640028.1 | n.*1244G>C | 3_prime_UTR_variant | Exon 16 of 35 | 5 | ENSP00000491488.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152030Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000397 AC: 6AN: 151142Hom.: 0 AF XY: 0.0000608 AC XY: 5AN XY: 82242
GnomAD4 exome AF: 0.0000150 AC: 21AN: 1398290Hom.: 0 Cov.: 33 AF XY: 0.0000159 AC XY: 11AN XY: 690702
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74380
ClinVar
Submissions by phenotype
Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
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Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1111 of the CACNA1H protein (p.Gly1111Arg). This variant is present in population databases (rs59529743, gnomAD 0.02%). 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: 572432). 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. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at