GeneBe

NM_000719.7:c.1384C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_000719.7(CACNA1C):​c.1384C>A​(p.Arg462Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,092 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.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.90

Publications

2 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]
CACNA1C Gene-Disease associations (from GenCC):
  • Timothy syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • long QT syndrome
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • long QT syndrome 8
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • Brugada syndrome
    Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
  • Brugada syndrome 3
    Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • intellectual disability
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • short QT syndrome
    Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.19).
BP7
Synonymous conserved (PhyloP=1.9 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 ENST00000399655.6 NP_000710.5
CACNA1CNM_001167623.2 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 ENST00000399603.6 NP_001161095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 5 NM_001167623.2 ENSP00000382512.1
CACNA1CENST00000399655.6 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 NM_000719.7 ENSP00000382563.1
CACNA1CENST00000682544.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 50 ENSP00000507184.1
CACNA1CENST00000406454.8 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 5 ENSP00000385896.3
CACNA1CENST00000399634.6 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 5 ENSP00000382542.2
CACNA1CENST00000683824.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 48 ENSP00000507867.1
CACNA1CENST00000347598.9 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 49 1 ENSP00000266376.6
CACNA1CENST00000344100.7 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000341092.3
CACNA1CENST00000327702.12 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 1 ENSP00000329877.7
CACNA1CENST00000399617.6 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 5 ENSP00000382526.1
CACNA1CENST00000682462.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 47 ENSP00000507105.1
CACNA1CENST00000683781.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 47 ENSP00000507434.1
CACNA1CENST00000683840.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 47 ENSP00000507612.1
CACNA1CENST00000683956.1 linkc.1474C>A p.Arg492Arg synonymous_variant Exon 9 of 47 ENSP00000506882.1
CACNA1CENST00000399638.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 1 ENSP00000382547.1
CACNA1CENST00000335762.10 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 5 ENSP00000336982.5
CACNA1CENST00000399606.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 48 1 ENSP00000382515.1
CACNA1CENST00000399621.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382530.1
CACNA1CENST00000399637.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382546.1
CACNA1CENST00000402845.7 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000385724.3
CACNA1CENST00000399629.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382537.1
CACNA1CENST00000682336.1 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 ENSP00000507898.1
CACNA1CENST00000399591.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 46 1 ENSP00000382500.1
CACNA1CENST00000399595.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 46 1 ENSP00000382504.1
CACNA1CENST00000399649.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 46 1 ENSP00000382557.1
CACNA1CENST00000399597.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382506.1
CACNA1CENST00000399601.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382510.1
CACNA1CENST00000399641.6 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382549.1
CACNA1CENST00000399644.5 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 1 ENSP00000382552.1
CACNA1CENST00000682835.1 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 47 ENSP00000507282.1
CACNA1CENST00000683482.1 linkc.1375C>A p.Arg459Arg synonymous_variant Exon 9 of 47 ENSP00000507169.1
CACNA1CENST00000682686.1 linkc.1384C>A p.Arg462Arg synonymous_variant Exon 9 of 46 ENSP00000507309.1
CACNA1CENST00000480911.6 linkn.1113+19592C>A intron_variant Intron 7 of 26 5 ENSP00000437936.2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000133
AC:
3
AN:
225186
AF XY:
0.0000247
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000608
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000991
Gnomad OTH exome
AF:
0.000179
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1448092
Hom.:
0
Cov.:
30
AF XY:
0.00000139
AC XY:
1
AN XY:
718918
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33246
American (AMR)
AF:
0.00
AC:
0
AN:
42872
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25784
East Asian (EAS)
AF:
0.0000255
AC:
1
AN:
39158
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83472
European-Finnish (FIN)
AF:
0.0000190
AC:
1
AN:
52540
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1105360
Other (OTH)
AF:
0.00
AC:
0
AN:
59926
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
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.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.19
CADD
Benign
13
DANN
Benign
0.73
PhyloP100
1.9

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: rs761430418; hg19: chr12-2622144; API