rs60734921
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BS1BS2
The NM_021098.3(CACNA1H):c.1853C>T(p.Pro618Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,585,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.
Frequency
Consequence
NM_021098.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1H | NM_021098.3 | c.1853C>T | p.Pro618Leu | missense_variant | 9/35 | ENST00000348261.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.1853C>T | p.Pro618Leu | missense_variant | 9/35 | 1 | NM_021098.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000480 AC: 73AN: 152186Hom.: 1 Cov.: 34
GnomAD3 exomes AF: 0.000536 AC: 105AN: 196016Hom.: 0 AF XY: 0.000493 AC XY: 53AN XY: 107556
GnomAD4 exome AF: 0.000966 AC: 1384AN: 1432760Hom.: 2 Cov.: 57 AF XY: 0.000970 AC XY: 689AN XY: 710164
GnomAD4 genome ? AF: 0.000479 AC: 73AN: 152304Hom.: 1 Cov.: 34 AF XY: 0.000497 AC XY: 37AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2015 | The P618L variant in the CACNA1H gene has been reported previously in association with familial cases of epilepsy; however, this variant did not segregate with the disease in all families reported (Heron et al., 2004; Heron et al., 2007). The P618L variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P618L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional characterization of P618L indicates that this variant results in accelerated channel activation as well as channel inactivation, thereby allowing for greater channel availability of P618L compared to wild type (Khosravani et al., 2005). We interpret P618L as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 14, 2018 | - - |
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | - - |
Epilepsy, idiopathic generalized, susceptibility to, 6 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at