rs763045560
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001127222.2(CACNA1A):c.6527G>T(p.Gly2176Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,536,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001127222.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.6527G>T | p.Gly2176Val | missense_variant, splice_region_variant | Exon 46 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.6545G>T | p.Gly2182Val | missense_variant, splice_region_variant | Exon 47 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.6533G>T | p.Gly2178Val | missense_variant, splice_region_variant | Exon 46 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.6530G>T | p.Gly2177Val | missense_variant, splice_region_variant | Exon 46 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.6530G>T | p.Gly2177Val | missense_variant, splice_region_variant | Exon 46 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.6494G>T | p.Gly2165Val | missense_variant, splice_region_variant | Exon 45 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.6389G>T | p.Gly2130Val | missense_variant, splice_region_variant | Exon 45 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.6530G>T | p.Gly2177Val | missense_variant, splice_region_variant | Exon 46 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.6545G>T | p.Gly2182Val | missense_variant, splice_region_variant | Exon 47 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.6536G>T | p.Gly2179Val | missense_variant, splice_region_variant | Exon 47 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.6533G>T | p.Gly2178Val | missense_variant, splice_region_variant | Exon 46 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.6530G>T | p.Gly2177Val | missense_variant, splice_region_variant | Exon 46 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.6530G>T | p.Gly2177Val | missense_variant, splice_region_variant | Exon 46 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.6494G>T | p.Gly2165Val | missense_variant, splice_region_variant | Exon 45 of 46 | 5 | ENSP00000489777.1 | |||
CACNA1A | ENST00000636768.1 | n.*793G>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 10 of 10 | 5 | ENSP00000490190.2 | ||||
CACNA1A | ENST00000636768.1 | n.*793G>T | 3_prime_UTR_variant | Exon 10 of 10 | 5 | ENSP00000490190.2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32
GnomAD4 exome AF: 7.22e-7 AC: 1AN: 1384812Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 683402
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:2
The CACNA1A c.6530G>T; p.Gly2177Val variant (rs763045560), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 424463). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.499). However, this variant is located at the end of an exon and computational analyses (Alamut Visual Plus v.1.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2177 of the CACNA1A protein (p.Gly2177Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 424463). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Inborn genetic diseases Uncertain:1
The p.G2177V variant (also known as c.6530G>T) is located in coding exon 46 of the CACNA1A gene. The glycine at codon 2177 is replaced by valine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 46. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Developmental and epileptic encephalopathy, 42 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with CACNA1A-related disease. Episodic ataxia, type 2 (MIM#108500) is caused by variants with a loss of function mechanism (PMID: 28566750). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for patients with episodic ataxia, type 2 (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Two families with episodic ataxia, intellectual disability and/or epilepsy have been reported with intrafamilial variability (PMID: 32910250, PMID: 30142438). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Undetermined early-onset epileptic encephalopathy Uncertain:1
This sequence change in CACNA1A is predicted to replace glycine with valine at codon 2176, p.(Gly2176Val). The glycine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the cytoplasmic domain. There is a large physicochemical difference between glycine and valine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.016% (8/50,972 alleles) in the Admixed American population. To our knowledge, this variant has not been previously reported in the relevant scientific literature. Computational evidence is uninformative for the missense substitution (REVEL = 0.499). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at