GeneBe

rs181892888

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_021098.3(CACNA1H):​c.2030C>A​(p.Ser677*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000141 in 1,418,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S677S) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 stop_gained

Scores

4
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.19

Publications

0 publications found
Variant links:
Genes affected
CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]
CACNA1H Gene-Disease associations (from GenCC):
  • hyperaldosteronism, familial, type IV
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • childhood absence epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • epilepsy, childhood absence, susceptibility to, 6
    Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 ENST00000348261.11 NP_066921.2 O95180-1B3KQH9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1HENST00000348261.11 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.1991C>A p.Ser664* stop_gained Exon 10 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.1991C>A p.Ser664* stop_gained Exon 10 of 34 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.2030C>A p.Ser677* stop_gained Exon 10 of 34 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 37 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.1413C>A non_coding_transcript_exon_variant Exon 10 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*1477C>A non_coding_transcript_exon_variant Exon 9 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.2030C>A non_coding_transcript_exon_variant Exon 10 of 35 ENSP00000518777.1
CACNA1HENST00000711442.1 linkn.*1477C>A 3_prime_UTR_variant Exon 9 of 34 ENSP00000518758.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000141
AC:
2
AN:
1418566
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
701814
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:
32444
American (AMR)
AF:
0.00
AC:
0
AN:
39524
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25378
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37300
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47224
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5704
European-Non Finnish (NFE)
AF:
0.00000183
AC:
2
AN:
1090942
Other (OTH)
AF:
0.00
AC:
0
AN:
58794
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
1
2
2
3
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
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
47
DANN
Uncertain
1.0
Eigen
Pathogenic
0.82
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
7.2
Vest4
0.59
GERP RS
4.3
Mutation Taster
=6/194
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs181892888; hg19: chr16-1254037; COSMIC: COSV61984210; COSMIC: COSV61984210; API