12-2053565-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_000719.7(CACNA1C):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CACNA1C
NM_000719.7 start_lost

Scores

8
2
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87
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 Uncertain_significance. 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.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.3G>C p.Met1? start_lost Exon 1 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.3G>C p.Met1? start_lost 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.3G>C p.Met1? start_lost Exon 1 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000406454.8 linkc.3G>C p.Met1? start_lost Exon 1 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.3G>C p.Met1? start_lost Exon 1 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000347598.9 linkc.3G>C p.Met1? start_lost Exon 1 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.3G>C p.Met1? start_lost Exon 1 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.3G>C p.Met1? start_lost Exon 1 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000399638.5 linkc.3G>C p.Met1? start_lost Exon 1 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.3G>C p.Met1? start_lost Exon 1 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.3G>C p.Met1? start_lost Exon 1 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.3G>C p.Met1? start_lost Exon 1 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.3G>C p.Met1? start_lost Exon 1 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.3G>C p.Met1? start_lost Exon 1 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.3G>C p.Met1? start_lost Exon 1 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.3G>C p.Met1? start_lost Exon 1 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.3G>C p.Met1? start_lost Exon 1 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.3G>C p.Met1? start_lost Exon 1 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.3G>C p.Met1? start_lost Exon 1 of 46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000682544.1 linkc.140-61659G>C intron_variant Intron 1 of 49 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000683824.1 linkc.140-61659G>C intron_variant Intron 1 of 47 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000682462.1 linkc.140-61659G>C intron_variant Intron 1 of 46 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.140-61659G>C intron_variant Intron 1 of 46 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.140-61659G>C intron_variant Intron 1 of 46 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.140-61659G>C intron_variant Intron 1 of 46 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000480911.6 linkn.3G>C non_coding_transcript_exon_variant Exon 1 of 27 5 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Mar 05, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; however, in the absence of functional evidence the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.016
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Benign
0.14
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.91
D
M_CAP
Pathogenic
0.96
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
Pathogenic
0.88
D
PROVEAN
Benign
-0.74
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Pathogenic
0.71
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
0.39, 0.025, 0.11, 0.66
.;B;.;B;B;B;B;B;B;B;B;P;B;B;B;B;.;B;B;.;.;.;.
Vest4
0.89
MutPred
0.98
Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);
MVP
0.98
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2162731; API