rs1060503449
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000480911.6(CACNA1C):n.*2441C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,541,562 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
CACNA1C
ENST00000480911.6 non_coding_transcript_exon
ENST00000480911.6 non_coding_transcript_exon
Scores
2
Splicing: ADA: 0.0001588
2
Clinical Significance
Conservation
PhyloP100: 0.841
Publications
0 publications found
Genes affected
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
CACNA1C Gene-Disease associations (from GenCC):
- Timothy syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizuresInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- long QT syndromeInheritance: AD Classification: MODERATE Submitted by: ClinGen
- long QT syndrome 8Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- Brugada syndromeInheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
- Brugada syndrome 3Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- intellectual disabilityInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- short QT syndromeInheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.3).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1C | NM_000719.7 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENST00000399655.6 | NP_000710.5 | ||
| CACNA1C | NM_001167623.2 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1C | ENST00000480911.6 | n.*2441C>T | non_coding_transcript_exon_variant | Exon 27 of 27 | 5 | ENSP00000437936.2 | ||||
| CACNA1C | ENST00000480911.6 | n.*2441C>T | 3_prime_UTR_variant | Exon 27 of 27 | 5 | ENSP00000437936.2 | ||||
| CACNA1C | ENST00000399603.6 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 5 | NM_001167623.2 | ENSP00000382512.1 | |||
| CACNA1C | ENST00000399655.6 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | NM_000719.7 | ENSP00000382563.1 | |||
| CACNA1C | ENST00000682544.1 | c.3978+6C>T | splice_region_variant, intron_variant | Intron 30 of 49 | ENSP00000507184.1 | |||||
| CACNA1C | ENST00000406454.8 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 47 | 5 | ENSP00000385896.3 | ||||
| CACNA1C | ENST00000399634.6 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 5 | ENSP00000382542.2 | ||||
| CACNA1C | ENST00000683824.1 | c.3993+6C>T | splice_region_variant, intron_variant | Intron 30 of 47 | ENSP00000507867.1 | |||||
| CACNA1C | ENST00000347598.9 | c.3888+6C>T | splice_region_variant, intron_variant | Intron 30 of 48 | 1 | ENSP00000266376.6 | ||||
| CACNA1C | ENST00000344100.7 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000341092.3 | ||||
| CACNA1C | ENST00000327702.12 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 47 | 1 | ENSP00000329877.7 | ||||
| CACNA1C | ENST00000399617.6 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 47 | 5 | ENSP00000382526.1 | ||||
| CACNA1C | ENST00000682462.1 | c.3918+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000507105.1 | |||||
| CACNA1C | ENST00000683781.1 | c.3918+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000507434.1 | |||||
| CACNA1C | ENST00000683840.1 | c.3918+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000507612.1 | |||||
| CACNA1C | ENST00000683956.1 | c.3918+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000506882.1 | |||||
| CACNA1C | ENST00000399638.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 47 | 1 | ENSP00000382547.1 | ||||
| CACNA1C | ENST00000335762.10 | c.3903+6C>T | splice_region_variant, intron_variant | Intron 30 of 47 | 5 | ENSP00000336982.5 | ||||
| CACNA1C | ENST00000399606.5 | c.3888+6C>T | splice_region_variant, intron_variant | Intron 30 of 47 | 1 | ENSP00000382515.1 | ||||
| CACNA1C | ENST00000399621.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382530.1 | ||||
| CACNA1C | ENST00000399637.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382546.1 | ||||
| CACNA1C | ENST00000402845.7 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000385724.3 | ||||
| CACNA1C | ENST00000399629.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382537.1 | ||||
| CACNA1C | ENST00000682336.1 | c.3903+6C>T | splice_region_variant, intron_variant | Intron 30 of 46 | ENSP00000507898.1 | |||||
| CACNA1C | ENST00000399591.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 45 | 1 | ENSP00000382500.1 | ||||
| CACNA1C | ENST00000399595.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 45 | 1 | ENSP00000382504.1 | ||||
| CACNA1C | ENST00000399649.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 45 | 1 | ENSP00000382557.1 | ||||
| CACNA1C | ENST00000399597.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382506.1 | ||||
| CACNA1C | ENST00000399601.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382510.1 | ||||
| CACNA1C | ENST00000399641.6 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382549.1 | ||||
| CACNA1C | ENST00000399644.5 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | 1 | ENSP00000382552.1 | ||||
| CACNA1C | ENST00000682835.1 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000507282.1 | |||||
| CACNA1C | ENST00000683482.1 | c.3819+6C>T | splice_region_variant, intron_variant | Intron 29 of 46 | ENSP00000507169.1 | |||||
| CACNA1C | ENST00000682686.1 | c.3828+6C>T | splice_region_variant, intron_variant | Intron 29 of 45 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152072
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 7.20e-7 AC: 1AN: 1389490Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 695638 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1389490
Hom.:
Cov.:
23
AF XY:
AC XY:
0
AN XY:
695638
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
31976
American (AMR)
AF:
AC:
0
AN:
44608
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25682
East Asian (EAS)
AF:
AC:
0
AN:
39296
South Asian (SAS)
AF:
AC:
0
AN:
84704
European-Finnish (FIN)
AF:
AC:
0
AN:
53298
Middle Eastern (MID)
AF:
AC:
0
AN:
5620
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1046242
Other (OTH)
AF:
AC:
0
AN:
58064
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152072
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74288
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41400
American (AMR)
AF:
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5182
South Asian (SAS)
AF:
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68008
Other (OTH)
AF:
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome Uncertain:1
Nov 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is present in population databases (no rsID available, gnomAD 0.01%). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 411733). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change falls in intron 29 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.