rs757172314
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000719.7(CACNA1C):c.5622_5624delGGA(p.Glu1874del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000131 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CACNA1C
NM_000719.7 disruptive_inframe_deletion
NM_000719.7 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.35
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000719.7. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CACNA1C | NM_000719.7 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | ENST00000399655.6 | NP_000710.5 | |
| CACNA1C | NM_001167623.2 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | ENST00000399603.6 | NP_001161095.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CACNA1C | ENST00000399603.6 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 5 | NM_001167623.2 | ENSP00000382512.1 | ||
| CACNA1C | ENST00000399655.6 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 1 | NM_000719.7 | ENSP00000382563.1 | ||
| CACNA1C | ENST00000682544.1 | c.5961_5963delGGA | p.Glu1987del | disruptive_inframe_deletion | 47/50 | ENSP00000507184.1 | ||||
| CACNA1C | ENST00000406454.8 | c.5835_5837delGGA | p.Glu1945del | disruptive_inframe_deletion | 45/48 | 5 | ENSP00000385896.3 | |||
| CACNA1C | ENST00000399634.6 | c.5802_5804delGGA | p.Glu1934del | disruptive_inframe_deletion | 44/47 | 5 | ENSP00000382542.2 | |||
| CACNA1C | ENST00000683824.1 | c.5787_5789delGGA | p.Glu1929del | disruptive_inframe_deletion | 45/48 | ENSP00000507867.1 | ||||
| CACNA1C | ENST00000347598.9 | c.5766_5768delGGA | p.Glu1922del | disruptive_inframe_deletion | 46/49 | 1 | ENSP00000266376.6 | |||
| CACNA1C | ENST00000344100.7 | c.5745_5747delGGA | p.Glu1915del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000341092.3 | |||
| CACNA1C | ENST00000327702.12 | c.5727_5729delGGA | p.Glu1909del | disruptive_inframe_deletion | 45/48 | 1 | ENSP00000329877.7 | |||
| CACNA1C | ENST00000399617.6 | c.5727_5729delGGA | p.Glu1909del | disruptive_inframe_deletion | 45/48 | 5 | ENSP00000382526.1 | |||
| CACNA1C | ENST00000682462.1 | c.5712_5714delGGA | p.Glu1904del | disruptive_inframe_deletion | 44/47 | ENSP00000507105.1 | ||||
| CACNA1C | ENST00000683781.1 | c.5712_5714delGGA | p.Glu1904del | disruptive_inframe_deletion | 44/47 | ENSP00000507434.1 | ||||
| CACNA1C | ENST00000683840.1 | c.5712_5714delGGA | p.Glu1904del | disruptive_inframe_deletion | 44/47 | ENSP00000507612.1 | ||||
| CACNA1C | ENST00000683956.1 | c.5712_5714delGGA | p.Glu1904del | disruptive_inframe_deletion | 44/47 | ENSP00000506882.1 | ||||
| CACNA1C | ENST00000399638.5 | c.5706_5708delGGA | p.Glu1902del | disruptive_inframe_deletion | 45/48 | 1 | ENSP00000382547.1 | |||
| CACNA1C | ENST00000335762.10 | c.5697_5699delGGA | p.Glu1899del | disruptive_inframe_deletion | 45/48 | 5 | ENSP00000336982.5 | |||
| CACNA1C | ENST00000399606.5 | c.5682_5684delGGA | p.Glu1894del | disruptive_inframe_deletion | 45/48 | 1 | ENSP00000382515.1 | |||
| CACNA1C | ENST00000399621.5 | c.5679_5681delGGA | p.Glu1893del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382530.1 | |||
| CACNA1C | ENST00000399637.5 | c.5679_5681delGGA | p.Glu1893del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382546.1 | |||
| CACNA1C | ENST00000402845.7 | c.5679_5681delGGA | p.Glu1893del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000385724.3 | |||
| CACNA1C | ENST00000399629.5 | c.5673_5675delGGA | p.Glu1891del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382537.1 | |||
| CACNA1C | ENST00000682336.1 | c.5664_5666delGGA | p.Glu1888del | disruptive_inframe_deletion | 44/47 | ENSP00000507898.1 | ||||
| CACNA1C | ENST00000399591.5 | c.5646_5648delGGA | p.Glu1882del | disruptive_inframe_deletion | 43/46 | 1 | ENSP00000382500.1 | |||
| CACNA1C | ENST00000399595.5 | c.5646_5648delGGA | p.Glu1882del | disruptive_inframe_deletion | 43/46 | 1 | ENSP00000382504.1 | |||
| CACNA1C | ENST00000399649.5 | c.5640_5642delGGA | p.Glu1880del | disruptive_inframe_deletion | 43/46 | 1 | ENSP00000382557.1 | |||
| CACNA1C | ENST00000399597.5 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382506.1 | |||
| CACNA1C | ENST00000399601.5 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382510.1 | |||
| CACNA1C | ENST00000399641.6 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382549.1 | |||
| CACNA1C | ENST00000399644.5 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | 1 | ENSP00000382552.1 | |||
| CACNA1C | ENST00000682835.1 | c.5622_5624delGGA | p.Glu1874del | disruptive_inframe_deletion | 44/47 | ENSP00000507282.1 | ||||
| CACNA1C | ENST00000683482.1 | c.5613_5615delGGA | p.Glu1871del | disruptive_inframe_deletion | 44/47 | ENSP00000507169.1 | ||||
| CACNA1C | ENST00000682686.1 | c.5589_5591delGGA | p.Glu1863del | disruptive_inframe_deletion | 43/46 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248938Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135052
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000116 AC: 17AN: 1461442Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727018
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
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 | Sep 20, 2021 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2021 | Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function - |
Long QT syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | This variant, c.5622_5624del, results in the deletion of 1 amino acid(s) of the CACNA1C protein (p.Glu1874del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757172314, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 411730). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2023 | The c.5622_5624delGGA variant (also known as p.E1874del) is located in coding exon 44 of the CACNA1C gene. This variant results from an in-frame GGA deletion at nucleotide positions 5622 to 5624. This results in the in-frame deletion of a glutamic acid at codon 1874. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at