GeneBe

16-1220129-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021098.3(CACNA1H):​c.6197G>T​(p.Ser2066Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S2066T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CACNA1H
NM_021098.3 missense

Scores

11
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.93

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 2 ACMG points.

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.6197G>T p.Ser2066Ile missense_variant Exon 35 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.6197G>T p.Ser2066Ile missense_variant Exon 35 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.6212G>T p.Ser2071Ile missense_variant Exon 34 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.6182G>T p.Ser2061Ile missense_variant Exon 34 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.6179G>T p.Ser2060Ile missense_variant Exon 34 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.6179G>T p.Ser2060Ile missense_variant Exon 35 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.6164G>T p.Ser2055Ile missense_variant Exon 35 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.6158G>T p.Ser2053Ile missense_variant Exon 35 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.6146G>T p.Ser2049Ile missense_variant Exon 34 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.6140G>T p.Ser2047Ile missense_variant Exon 34 of 34 ENSP00000518754.1
CACNA1HENST00000637236.3 linkn.*2116G>T non_coding_transcript_exon_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1245G>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4015G>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5641G>T non_coding_transcript_exon_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1138G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1056G>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*1776G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*864G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*831G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*111G>T non_coding_transcript_exon_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.6197G>T non_coding_transcript_exon_variant Exon 35 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.6164G>T non_coding_transcript_exon_variant Exon 35 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.*1313G>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000711483.1 linkc.*111G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.*111G>T 3_prime_UTR_variant Exon 34 of 34 ENSP00000518769.1
CACNA1HENST00000637236.3 linkn.*2116G>T 3_prime_UTR_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1245G>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4015G>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5641G>T 3_prime_UTR_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1138G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1056G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*1776G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*864G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*831G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*111G>T 3_prime_UTR_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711488.1 linkn.*1313G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000711482.1 linkc.6122-32G>T intron_variant Intron 35 of 35 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.6071-32G>T intron_variant Intron 34 of 34 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.6044-32G>T intron_variant Intron 35 of 35 ENSP00000518768.1
CACNA1HENST00000621827.2 linkn.6121+76G>T intron_variant Intron 35 of 36 6 ENSP00000518766.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
34
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
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1342234
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
657736
African (AFR)
AF:
0.00
AC:
0
AN:
27290
American (AMR)
AF:
0.00
AC:
0
AN:
29722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
20370
East Asian (EAS)
AF:
0.00
AC:
0
AN:
33786
South Asian (SAS)
AF:
0.00
AC:
0
AN:
66414
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48498
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5332
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1055596
Other (OTH)
AF:
0.00
AC:
0
AN:
55226
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152300
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74466
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41570
American (AMR)
AF:
0.00
AC:
0
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68004
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;.;.;.
Eigen
Benign
-0.046
Eigen_PC
Benign
-0.079
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.78
T;T;T;.
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.46
T;T;T;T
MetaSVM
Uncertain
0.37
D
MutationAssessor
Uncertain
2.8
M;.;.;.
PhyloP100
3.9
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.9
D;.;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.0070
D;.;D;D
Sift4G
Benign
0.23
T;.;T;T
Polyphen
0.76
P;.;P;P
Vest4
0.17
MutPred
0.25
Loss of phosphorylation at S2066 (P = 0.0072);.;.;.;
MVP
0.87
ClinPred
0.98
D
GERP RS
4.6
Varity_R
0.53
gMVP
0.55
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs369917102; hg19: chr16-1270129; API