NM_000719.7:c.6272A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000719.7(CACNA1C):​c.6272A>C​(p.Asn2091Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2091S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

6
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.21

Publications

0 publications found
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]
ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)
CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.265633).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 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.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.6611A>C p.Asn2204Thr missense_variant Exon 50 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.6485A>C p.Asn2162Thr missense_variant Exon 48 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.6452A>C p.Asn2151Thr missense_variant Exon 47 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.6437A>C p.Asn2146Thr missense_variant Exon 48 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.6416A>C p.Asn2139Thr missense_variant Exon 49 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.6395A>C p.Asn2132Thr missense_variant Exon 47 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.6377A>C p.Asn2126Thr missense_variant Exon 48 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.6377A>C p.Asn2126Thr missense_variant Exon 48 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.6362A>C p.Asn2121Thr missense_variant Exon 47 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.6362A>C p.Asn2121Thr missense_variant Exon 47 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.6362A>C p.Asn2121Thr missense_variant Exon 47 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.6362A>C p.Asn2121Thr missense_variant Exon 47 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.6356A>C p.Asn2119Thr missense_variant Exon 48 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.6347A>C p.Asn2116Thr missense_variant Exon 48 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.6332A>C p.Asn2111Thr missense_variant Exon 48 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.6329A>C p.Asn2110Thr missense_variant Exon 47 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.6329A>C p.Asn2110Thr missense_variant Exon 47 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.6329A>C p.Asn2110Thr missense_variant Exon 47 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.6323A>C p.Asn2108Thr missense_variant Exon 47 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.6314A>C p.Asn2105Thr missense_variant Exon 47 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.6296A>C p.Asn2099Thr missense_variant Exon 46 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.6296A>C p.Asn2099Thr missense_variant Exon 46 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.6290A>C p.Asn2097Thr missense_variant Exon 46 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.6272A>C p.Asn2091Thr missense_variant Exon 47 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.6263A>C p.Asn2088Thr missense_variant Exon 47 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.6239A>C p.Asn2080Thr missense_variant Exon 46 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455080
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
723254
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33338
American (AMR)
AF:
0.00
AC:
0
AN:
43772
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25950
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39408
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84954
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52694
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1109142
Other (OTH)
AF:
0.00
AC:
0
AN:
60070
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
CardioboostArm
Benign
0.0000082
BayesDel_addAF
Benign
-0.096
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.064
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.91
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.27
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.74
T
PhyloP100
3.2
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL
Benign
0.17
Sift
Benign
0.097
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.19
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
1.0, 0.048, 0.91, 0.0010, 1.0, 0.036, 0.99, 1.0, 1.0, 0.041
.;D;B;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;B;.
Vest4
0.31
MVP
0.58
MPC
0.54
ClinPred
0.96
D
GERP RS
4.5
gMVP
0.68
Mutation Taster
=59/41
polymorphism

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

Other links and lift over

dbSNP: rs201090446; hg19: chr12-2800220; API