12-2664928-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000719.7(CACNA1C):​c.4336C>T​(p.Pro1446Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

3
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.774
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ: 6.4654 (greater than the threshold 3.09). Trascript score misZ: 7.2674 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
BP4
Computational evidence support a benign effect (MetaRNN=0.21540222).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkc.4336C>T p.Pro1446Ser missense_variant 35/47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.4336C>T p.Pro1446Ser missense_variant 35/47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.4336C>T p.Pro1446Ser missense_variant 35/475 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.4570C>T p.Pro1524Ser missense_variant 37/50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.4336C>T p.Pro1446Ser missense_variant 35/485 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.4303C>T p.Pro1435Ser missense_variant 34/475 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.4501C>T p.Pro1501Ser missense_variant 36/48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.4480C>T p.Pro1494Ser missense_variant 37/491 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.4402C>T p.Pro1468Ser missense_variant 35/471 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.4336C>T p.Pro1446Ser missense_variant 35/481 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.4336C>T p.Pro1446Ser missense_variant 35/485 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.4426C>T p.Pro1476Ser missense_variant 35/47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.4426C>T p.Pro1476Ser missense_variant 35/47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.4426C>T p.Pro1476Ser missense_variant 35/47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.4426C>T p.Pro1476Ser missense_variant 35/47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.4420C>T p.Pro1474Ser missense_variant 36/481 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.4411C>T p.Pro1471Ser missense_variant 36/485 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.4396C>T p.Pro1466Ser missense_variant 36/481 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.4387C>T p.Pro1463Ser missense_variant 35/471 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.4378C>T p.Pro1460Ser missense_variant 35/47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.4303C>T p.Pro1435Ser missense_variant 34/461 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.4303C>T p.Pro1435Ser missense_variant 34/461 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.4297C>T p.Pro1433Ser missense_variant 34/461 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.4336C>T p.Pro1446Ser missense_variant 35/471 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.4336C>T p.Pro1446Ser missense_variant 35/47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.4327C>T p.Pro1443Ser missense_variant 35/47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.4303C>T p.Pro1435Ser missense_variant 34/46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250232
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135532
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461778
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.28
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.40
N
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.22
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.060
D
MutationAssessor
Benign
-0.73
.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.75
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Uncertain
0.32
Sift
Benign
0.37
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.37
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0, 0.0010, 0.22, 0.018
.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4
0.14
MutPred
0.48
.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1497 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.55
MPC
1.1
ClinPred
0.069
T
GERP RS
3.2
gMVP
0.72

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: rs758143691; hg19: chr12-2774094; API