chr12-2669044-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000719.7(CACNA1C):c.4726+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,583,480 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 Benign (★★).
Frequency
Consequence
NM_000719.7 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 5 | NM_001167623.2 | ENSP00000382512.1 | |||
CACNA1C | ENST00000399655.6 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | NM_000719.7 | ENSP00000382563.1 | |||
CACNA1C | ENST00000682544.1 | c.4960+9G>A | intron_variant | Intron 40 of 49 | ENSP00000507184.1 | |||||
CACNA1C | ENST00000406454.8 | c.4726+9G>A | intron_variant | Intron 38 of 47 | 5 | ENSP00000385896.3 | ||||
CACNA1C | ENST00000399634.6 | c.4693+9G>A | intron_variant | Intron 37 of 46 | 5 | ENSP00000382542.2 | ||||
CACNA1C | ENST00000683824.1 | c.4891+9G>A | intron_variant | Intron 39 of 47 | ENSP00000507867.1 | |||||
CACNA1C | ENST00000347598.9 | c.4870+9G>A | intron_variant | Intron 40 of 48 | 1 | ENSP00000266376.6 | ||||
CACNA1C | ENST00000344100.7 | c.4792+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000341092.3 | ||||
CACNA1C | ENST00000327702.12 | c.4726+9G>A | intron_variant | Intron 38 of 47 | 1 | ENSP00000329877.7 | ||||
CACNA1C | ENST00000399617.6 | c.4726+9G>A | intron_variant | Intron 38 of 47 | 5 | ENSP00000382526.1 | ||||
CACNA1C | ENST00000682462.1 | c.4816+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507105.1 | |||||
CACNA1C | ENST00000683781.1 | c.4816+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507434.1 | |||||
CACNA1C | ENST00000683840.1 | c.4816+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507612.1 | |||||
CACNA1C | ENST00000683956.1 | c.4816+9G>A | intron_variant | Intron 38 of 46 | ENSP00000506882.1 | |||||
CACNA1C | ENST00000399638.5 | c.4810+9G>A | intron_variant | Intron 39 of 47 | 1 | ENSP00000382547.1 | ||||
CACNA1C | ENST00000335762.10 | c.4801+9G>A | intron_variant | Intron 39 of 47 | 5 | ENSP00000336982.5 | ||||
CACNA1C | ENST00000399606.5 | c.4786+9G>A | intron_variant | Intron 39 of 47 | 1 | ENSP00000382515.1 | ||||
CACNA1C | ENST00000399621.5 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382530.1 | ||||
CACNA1C | ENST00000399637.5 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382546.1 | ||||
CACNA1C | ENST00000402845.7 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000385724.3 | ||||
CACNA1C | ENST00000399629.5 | c.4777+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382537.1 | ||||
CACNA1C | ENST00000682336.1 | c.4768+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507898.1 | |||||
CACNA1C | ENST00000399591.5 | c.4693+9G>A | intron_variant | Intron 37 of 45 | 1 | ENSP00000382500.1 | ||||
CACNA1C | ENST00000399595.5 | c.4693+9G>A | intron_variant | Intron 37 of 45 | 1 | ENSP00000382504.1 | ||||
CACNA1C | ENST00000399649.5 | c.4687+9G>A | intron_variant | Intron 37 of 45 | 1 | ENSP00000382557.1 | ||||
CACNA1C | ENST00000399597.5 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382506.1 | ||||
CACNA1C | ENST00000399601.5 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382510.1 | ||||
CACNA1C | ENST00000399641.6 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382549.1 | ||||
CACNA1C | ENST00000399644.5 | c.4726+9G>A | intron_variant | Intron 38 of 46 | 1 | ENSP00000382552.1 | ||||
CACNA1C | ENST00000682835.1 | c.4726+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507282.1 | |||||
CACNA1C | ENST00000683482.1 | c.4717+9G>A | intron_variant | Intron 38 of 46 | ENSP00000507169.1 | |||||
CACNA1C | ENST00000682686.1 | c.4693+9G>A | intron_variant | Intron 37 of 45 | ENSP00000507309.1 |
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000204 AC: 51AN: 249784Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135500
GnomAD4 exome AF: 0.000306 AC: 438AN: 1431184Hom.: 0 Cov.: 25 AF XY: 0.000291 AC XY: 208AN XY: 713986
GnomAD4 genome AF: 0.000236 AC: 36AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74472
ClinVar
Submissions by phenotype
not specified Benign:2
Variant summary: CACNA1C c.4726+9G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 249784 control chromosomes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4726+9G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
CACNA1C-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). -
Long QT syndrome Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at