rs1555774889

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_000719.7(CACNA1C):​c.1410G>T​(p.Glu470Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 missense

Scores

3
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64
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 4 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
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=0.31952465).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1CNM_000719.7 linkc.1410G>T p.Glu470Asp missense_variant 10/47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.1410G>T p.Glu470Asp missense_variant 10/47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.1410G>T p.Glu470Asp missense_variant 10/475 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.1410G>T p.Glu470Asp missense_variant 10/471 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.1500G>T p.Glu500Asp missense_variant 10/50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.1410G>T p.Glu470Asp missense_variant 10/485 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.1410G>T p.Glu470Asp missense_variant 10/475 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.1575G>T p.Glu525Asp missense_variant 11/48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.1410G>T p.Glu470Asp missense_variant 10/491 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.1410G>T p.Glu470Asp missense_variant 10/481 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.1410G>T p.Glu470Asp missense_variant 10/485 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.1500G>T p.Glu500Asp missense_variant 10/47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.1500G>T p.Glu500Asp missense_variant 10/47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.1500G>T p.Glu500Asp missense_variant 10/47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.1500G>T p.Glu500Asp missense_variant 10/47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.1410G>T p.Glu470Asp missense_variant 10/481 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.1485G>T p.Glu495Asp missense_variant 11/485 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.1410G>T p.Glu470Asp missense_variant 10/481 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.1485G>T p.Glu495Asp missense_variant 11/47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.1410G>T p.Glu470Asp missense_variant 10/461 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.1410G>T p.Glu470Asp missense_variant 10/461 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.1410G>T p.Glu470Asp missense_variant 10/461 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.1410G>T p.Glu470Asp missense_variant 10/471 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.1410G>T p.Glu470Asp missense_variant 10/47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.1401G>T p.Glu467Asp missense_variant 10/47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.1410G>T p.Glu470Asp missense_variant 10/46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000480911.6 linkn.*17G>T non_coding_transcript_exon_variant 8/275 ENSP00000437936.2 F5H638
CACNA1CENST00000480911.6 linkn.*17G>T 3_prime_UTR_variant 8/275 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1452956
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
721762
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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), LabcorpDec 05, 2017In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 470 of the CACNA1C protein (p.Glu470Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.023
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Uncertain
0.090
D
MetaRNN
Benign
0.32
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
0.59
D
MutationAssessor
Benign
0.88
.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.7
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
0.55
Sift
Benign
0.34
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.38
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, 0.86, 0.72, 0.99, 0.0040, 1.0, 0.99, 0.47, 0.99, 1.0, 0.025, 0.95
.;D;P;P;D;B;D;D;D;P;D;D;D;D;B;D;.;D;D;.;.;.;P
Vest4
0.49
MutPred
0.18
.;Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);
MVP
0.88
MPC
0.96
ClinPred
0.58
D
GERP RS
5.1
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1555774889; hg19: chr12-2659128; API