GeneBe

rs377612703

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000711493.1(CACNA1H):​c.4381C>A​(p.Arg1461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1461C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
ENST00000711493.1 missense

Scores

2
Splicing: ADA: 0.9922
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.164

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: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENST00000348261.11 NP_066921.2 O95180-1B3KQH9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1HENST00000711493.1 linkc.4381C>A p.Arg1461Ser missense_variant Exon 23 of 34 ENSP00000518778.1
CACNA1HENST00000348261.11 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 33 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000565831.7 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.4312-6C>A splice_region_variant, intron_variant Intron 22 of 34 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 33 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.4312-6C>A splice_region_variant, intron_variant Intron 22 of 33 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.4351-6C>A splice_region_variant, intron_variant Intron 22 of 33 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 36 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.*321-6C>A splice_region_variant, intron_variant Intron 22 of 33 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*2264-6C>A splice_region_variant, intron_variant Intron 22 of 34 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3798-6C>A splice_region_variant, intron_variant Intron 21 of 33 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 36 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 35 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.4351-6C>A splice_region_variant, intron_variant Intron 22 of 34 ENSP00000518777.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460100
Hom.:
0
Cov.:
35
AF XY:
0.00000275
AC XY:
2
AN XY:
726354
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33466
American (AMR)
AF:
0.00
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52106
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111660
Other (OTH)
AF:
0.00
AC:
0
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41440
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 13, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CACNA1H c.4351-6C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4351-6C>A in individuals affected with CACNA1H-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
10
DANN
Benign
0.47
PhyloP100
-0.16

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.75
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: 2
DS_AL_spliceai
0.75
Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs377612703; hg19: chr16-1261475; API