rs201861473

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_000719.7(CACNA1C):​c.5235C>A​(p.His1745Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1C
NM_000719.7 missense

Scores

3
7
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.384
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 Uncertain_significance. Variant got 4 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). GenCC has associacion of 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/47 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.5235C>A p.His1745Gln missense_variant 42/475 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/471 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkuse as main transcriptc.5469C>A p.His1823Gln missense_variant 44/50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/485 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkuse as main transcriptc.5202C>A p.His1734Gln missense_variant 41/475 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkuse as main transcriptc.5400C>A p.His1800Gln missense_variant 43/48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkuse as main transcriptc.5379C>A p.His1793Gln missense_variant 44/491 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkuse as main transcriptc.5358C>A p.His1786Gln missense_variant 42/471 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/481 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/485 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkuse as main transcriptc.5325C>A p.His1775Gln missense_variant 42/47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkuse as main transcriptc.5325C>A p.His1775Gln missense_variant 42/47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkuse as main transcriptc.5325C>A p.His1775Gln missense_variant 42/47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkuse as main transcriptc.5325C>A p.His1775Gln missense_variant 42/47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkuse as main transcriptc.5319C>A p.His1773Gln missense_variant 43/481 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkuse as main transcriptc.5310C>A p.His1770Gln missense_variant 43/485 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkuse as main transcriptc.5295C>A p.His1765Gln missense_variant 43/481 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkuse as main transcriptc.5292C>A p.His1764Gln missense_variant 42/471 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkuse as main transcriptc.5292C>A p.His1764Gln missense_variant 42/471 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkuse as main transcriptc.5292C>A p.His1764Gln missense_variant 42/471 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkuse as main transcriptc.5286C>A p.His1762Gln missense_variant 42/471 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkuse as main transcriptc.5277C>A p.His1759Gln missense_variant 42/47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkuse as main transcriptc.5259C>A p.His1753Gln missense_variant 41/461 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkuse as main transcriptc.5259C>A p.His1753Gln missense_variant 41/461 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkuse as main transcriptc.5253C>A p.His1751Gln missense_variant 41/461 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/471 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/471 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/471 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/471 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkuse as main transcriptc.5235C>A p.His1745Gln missense_variant 42/47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkuse as main transcriptc.5226C>A p.His1742Gln missense_variant 42/47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkuse as main transcriptc.5202C>A p.His1734Gln missense_variant 41/46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.017
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Benign
-0.023
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.65
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.78
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
0.43
D
MutationAssessor
Uncertain
2.5
.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Uncertain
0.57
Sift
Benign
0.052
T;T;D;T;D;T;D;T;T;T;D;D;T;D;T;D;D;D;D;D;D;D;.
Sift4G
Benign
0.24
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.99, 0.0090, 0.80, 0.65, 1.0, 0.010, 1.0, 0.81
.;D;B;P;P;D;D;D;B;D;D;D;D;P;D;.;D;D;.;.;.;D;.
Vest4
0.67
MutPred
0.18
.;.;.;.;.;.;.;.;.;.;Gain of glycosylation at P1791 (P = 0.1319);.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.97
MPC
0.24
ClinPred
0.93
D
GERP RS
1.5
gMVP
0.34

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: rs201861473; hg19: chr12-2788753; API