chr19-13286791-C-A
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_001127222.2(CACNA1A):c.3265G>T(p.Gly1089Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,612,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1089S) has been classified as Likely benign.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
Publications
- episodic ataxia type 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- undetermined early-onset epileptic encephalopathyInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
- developmental and epileptic encephalopathy, 42Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- migraine, familial hemiplegic, 1Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- spinocerebellar ataxia type 6Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- benign paroxysmal torticollis of infancyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial or sporadic hemiplegic migraineInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Lennox-Gastaut syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.3265G>T | p.Gly1089Cys | missense_variant | Exon 20 of 47 | 1 | NM_001127222.2 | ENSP00000353362.5 | ||
CACNA1A | ENST00000638029.1 | c.3277G>T | p.Gly1093Cys | missense_variant | Exon 20 of 48 | 5 | ENSP00000489829.1 | |||
CACNA1A | ENST00000573710.7 | c.3271G>T | p.Gly1091Cys | missense_variant | Exon 20 of 47 | 5 | ENSP00000460092.3 | |||
CACNA1A | ENST00000635727.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 47 | 5 | ENSP00000490001.1 | |||
CACNA1A | ENST00000637769.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 47 | 1 | ENSP00000489778.1 | |||
CACNA1A | ENST00000636012.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 46 | 5 | ENSP00000490223.1 | |||
CACNA1A | ENST00000637736.1 | c.3127G>T | p.Gly1043Cys | missense_variant | Exon 19 of 46 | 5 | ENSP00000489861.1 | |||
CACNA1A | ENST00000636389.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 47 | 5 | ENSP00000489992.1 | |||
CACNA1A | ENST00000637432.1 | c.3277G>T | p.Gly1093Cys | missense_variant | Exon 20 of 48 | 5 | ENSP00000490617.1 | |||
CACNA1A | ENST00000636549.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 48 | 5 | ENSP00000490578.1 | |||
CACNA1A | ENST00000637927.1 | c.3271G>T | p.Gly1091Cys | missense_variant | Exon 20 of 47 | 5 | ENSP00000489715.1 | |||
CACNA1A | ENST00000635895.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 47 | 5 | ENSP00000490323.1 | |||
CACNA1A | ENST00000638009.2 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 47 | 1 | ENSP00000489913.1 | |||
CACNA1A | ENST00000637276.1 | c.3268G>T | p.Gly1090Cys | missense_variant | Exon 20 of 46 | 5 | ENSP00000489777.1 | |||
CACNA1A | ENST00000636768.2 | n.3268G>T | non_coding_transcript_exon_variant | Exon 20 of 45 | 5 | ENSP00000490190.2 | ||||
CACNA1A | ENST00000713789.1 | n.3265G>T | non_coding_transcript_exon_variant | Exon 20 of 47 | ENSP00000519091.1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 151900Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000370 AC: 90AN: 242946 AF XY: 0.000392 show subpopulations
GnomAD4 exome AF: 0.000260 AC: 380AN: 1460522Hom.: 0 Cov.: 35 AF XY: 0.000252 AC XY: 183AN XY: 726586 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000171 AC: 26AN: 152018Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74306 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:5
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CACNA1A: PP2, BS1 -
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Episodic ataxia type 2 Uncertain:1
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Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as 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. -
CACNA1A-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at