16-1207426-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_021098.3(CACNA1H):​c.3059C>T​(p.Ala1020Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3059C>T p.Ala1020Val missense_variant Exon 14 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.3059C>T p.Ala1020Val missense_variant Exon 14 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.3059C>T p.Ala1020Val missense_variant Exon 13 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.3020C>T p.Ala1007Val missense_variant Exon 14 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000639478.1 linkn.3059C>T non_coding_transcript_exon_variant Exon 14 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*972C>T non_coding_transcript_exon_variant Exon 14 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000640028.1 linkn.*972C>T 3_prime_UTR_variant Exon 14 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151772
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
247050
Hom.:
0
AF XY:
0.0000297
AC XY:
4
AN XY:
134632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000581
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000269
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1460574
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
726566
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151772
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
74120
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000166
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Jun 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Jul 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1020 of the CACNA1H protein (p.Ala1020Val). This variant is present in population databases (rs771994752, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 2026123). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1H protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
D;.;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;.
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.77
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M;.;M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.1
D;.;D;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0090
D;.;D;D
Sift4G
Uncertain
0.0030
D;.;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.68
MutPred
0.39
Loss of disorder (P = 0.0725);.;Loss of disorder (P = 0.0725);Loss of disorder (P = 0.0725);
MVP
0.96
ClinPred
0.89
D
GERP RS
3.6
Varity_R
0.58
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.52
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.52
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771994752; hg19: chr16-1257426; COSMIC: COSV100672633; COSMIC: COSV100672633; API