12-2053563-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The NM_000719.7(CACNA1C):ā€‹c.1A>Cā€‹(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000692 in 1,444,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000069 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 initiator_codon

Scores

6
2
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 21 CDS bases. Genomic position: 2053583. Lost 0.003 part of the original CDS.
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000406454.8 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000347598.9 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000399638.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000682544.1 linkc.140-61661A>C intron_variant Intron 1 of 49 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000683824.1 linkc.140-61661A>C intron_variant Intron 1 of 47 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000682462.1 linkc.140-61661A>C intron_variant Intron 1 of 46 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.140-61661A>C intron_variant Intron 1 of 46 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.140-61661A>C intron_variant Intron 1 of 46 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.140-61661A>C intron_variant Intron 1 of 46 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000480911.6 linkn.1A>C non_coding_transcript_exon_variant Exon 1 of 27 5 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000692
AC:
10
AN:
1444082
Hom.:
0
Cov.:
32
AF XY:
0.00000558
AC XY:
4
AN XY:
716624
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000906
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

Intellectual disability Uncertain:1
Sep 10, 2020
Diagnostic Laboratory, Strasbourg University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.42
CADD
Benign
21
DANN
Benign
0.92
DEOGEN2
Benign
0.011
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
-0.071
Eigen_PC
Benign
-0.025
FATHMM_MKL
Benign
0.66
D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.78
D
PROVEAN
Benign
-0.42
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.10, 0.011, 0.26
.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;.
Vest4
0.85
MutPred
0.98
Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);Gain of catalytic residue at T6 (P = 0.095);
MVP
0.99
ClinPred
0.99
D
GERP RS
3.0
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs931964122; hg19: chr12-2162729; API