GeneBe

rs550612732

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000719.7(CACNA1C):​c.4232+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000634 in 1,576,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

2
Splicing: ADA: 0.0003018
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkuse as main transcriptc.4466+4G>A splice_region_variant, intron_variant ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkuse as main transcriptc.4199+4G>A splice_region_variant, intron_variant 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkuse as main transcriptc.4397+4G>A splice_region_variant, intron_variant ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkuse as main transcriptc.4376+4G>A splice_region_variant, intron_variant 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkuse as main transcriptc.4298+4G>A splice_region_variant, intron_variant 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkuse as main transcriptc.4322+4G>A splice_region_variant, intron_variant ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkuse as main transcriptc.4322+4G>A splice_region_variant, intron_variant ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkuse as main transcriptc.4322+4G>A splice_region_variant, intron_variant ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkuse as main transcriptc.4322+4G>A splice_region_variant, intron_variant ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkuse as main transcriptc.4316+4G>A splice_region_variant, intron_variant 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkuse as main transcriptc.4307+4G>A splice_region_variant, intron_variant 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkuse as main transcriptc.4292+4G>A splice_region_variant, intron_variant 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkuse as main transcriptc.4283+4G>A splice_region_variant, intron_variant 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkuse as main transcriptc.4274+4G>A splice_region_variant, intron_variant ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkuse as main transcriptc.4199+4G>A splice_region_variant, intron_variant 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkuse as main transcriptc.4199+4G>A splice_region_variant, intron_variant 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkuse as main transcriptc.4193+4G>A splice_region_variant, intron_variant 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkuse as main transcriptc.4232+4G>A splice_region_variant, intron_variant ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkuse as main transcriptc.4223+4G>A splice_region_variant, intron_variant ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkuse as main transcriptc.4199+4G>A splice_region_variant, intron_variant ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000809
AC:
2
AN:
247066
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133938
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000665
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000632
AC:
9
AN:
1423968
Hom.:
0
Cov.:
25
AF XY:
0.00000704
AC XY:
5
AN XY:
710468
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000940
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2018This sequence change falls in intron 34 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs550612732, ExAC 0.007%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 411738). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
CADD
Benign
20
DANN
Benign
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00030
dbscSNV1_RF
Benign
0.046
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs550612732; hg19: chr12-2764408; API