NM_021098.3:c.3559G>T

Variant summary

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

The NM_021098.3(CACNA1H):​c.3559G>T​(p.Gly1187Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,420 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. G1187R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
8
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3290148).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 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.3559G>T p.Gly1187Trp missense_variant Exon 17 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.3520G>T p.Gly1174Trp missense_variant Exon 17 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.3520G>T p.Gly1174Trp missense_variant Exon 17 of 34 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.3559G>T p.Gly1187Trp missense_variant Exon 17 of 34 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 37 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1472G>T non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3006G>T non_coding_transcript_exon_variant Exon 16 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.3559G>T non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518777.1
CACNA1HENST00000640028.1 linkn.*1472G>T 3_prime_UTR_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3006G>T 3_prime_UTR_variant Exon 16 of 34 ENSP00000518758.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.18e-7
AC:
1
AN:
1392420
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
687258
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:
30928
American (AMR)
AF:
0.00
AC:
0
AN:
35730
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24996
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35402
South Asian (SAS)
AF:
0.00
AC:
0
AN:
78986
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
44364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5678
European-Non Finnish (NFE)
AF:
9.27e-7
AC:
1
AN:
1078510
Other (OTH)
AF:
0.00
AC:
0
AN:
57826
⚠️ 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
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D;.;.;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.65
T;T;T;.
M_CAP
Pathogenic
0.87
D
MetaRNN
Benign
0.33
T;T;T;T
MetaSVM
Uncertain
0.35
D
MutationAssessor
Uncertain
2.3
M;.;M;M
PhyloP100
1.1
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.9
D;.;D;D
REVEL
Benign
0.28
Sift
Benign
0.030
D;.;D;D
Sift4G
Uncertain
0.0060
D;.;D;D
Polyphen
1.0
D;.;B;B
Vest4
0.45
MutPred
0.29
Loss of relative solvent accessibility (P = 0.0404);.;Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);
MVP
0.93
ClinPred
0.95
D
GERP RS
3.0
Varity_R
0.14
gMVP
0.46
Mutation Taster
=87/13
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: rs772258959; hg19: chr16-1259227; API