12-2688658-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2
The NM_000719.7(CACNA1C):c.5996C>T(p.Thr1999Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. T1999A) has been classified as Likely benign.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5996C>T | p.Thr1999Ile | missense_variant | 46/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.5996C>T | p.Thr1999Ile | missense_variant | 46/47 | ENST00000399603.6 | |
CACNA1C-AS1 | NR_045725.1 | n.333+1482G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5996C>T | p.Thr1999Ile | missense_variant | 46/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.5996C>T | p.Thr1999Ile | missense_variant | 46/47 | 1 | NM_000719.7 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.294+1482G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000566 AC: 14AN: 247404Hom.: 0 AF XY: 0.0000817 AC XY: 11AN XY: 134608
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461304Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24AN XY: 726976
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152332Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74482
ClinVar
Submissions by phenotype
Long qt syndrome 8 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Feb 15, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.6245C>T (p.Thr2082Ile) in CACNA1C gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Thr2082Ile variant is reported with the allele frequency (0.005%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Thr at position 2082 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Thr2082Ile in CACNA1C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS) - |
Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2017 | The p.T1999I variant (also known as c.5996C>T), located in coding exon 46 of the CACNA1C gene, results from a C to T substitution at nucleotide position 5996. The threonine at codon 1999 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at