rs572722130
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001127222.2(CACNA1A):c.6464G>T(p.Arg2155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,389,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2155H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.6464G>T | p.Arg2155Leu | missense_variant | 45/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.6464G>T | p.Arg2155Leu | missense_variant | 45/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000223 AC: 34AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000205 AC: 1AN: 48850Hom.: 0 AF XY: 0.0000404 AC XY: 1AN XY: 24770
GnomAD4 exome AF: 0.0000493 AC: 61AN: 1236972Hom.: 1 Cov.: 32 AF XY: 0.0000553 AC XY: 33AN XY: 597166
GnomAD4 genome ? AF: 0.000223 AC: 34AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 11, 2016 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2017 | A variant of uncertain significance has been identified in the CACNA1A gene. The R2156L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2156L variantis observed in 1/1162 (0.09%) alleles from individuals of Ashkenazi Jewish background and 3/12,428 (0.02%) alleles from individuals of African background, including 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The R2156L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 20, 2021 | Variant summary: CACNA1A c.6467G>T (p.Arg2156Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 150934 control chromosomes, predominantly at a frequency of 0.00058 (i.e. 24/41442 alleles) within the African or African-American subpopulation in the gnomAD v3.1 database. The number of occurrences is higher than expected for a pathogenic variant causing Early Infantile Epileptic Encephalopathy-42 (EE42), which tends to be a high penetrance, early onset disease (OMIM). To our knowledge, no occurrence of c.6467G>T in individuals affected with EE42 and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (1x). One of the ClinVar submitters cited evidence of lack of segregation with disease in a family study (SCV000848682.3) while another ClinVar submitter cited a homozygous occurrence of the variant in one individual undergoing testing (SCV000528812.3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at