rs376470846

Variant summary

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

The NM_021098.3(CACNA1H):ā€‹c.2931C>Gā€‹(p.Asn977Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,154 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.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 30)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

10
5
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.367
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
MetaRNN computational evidence supports a deleterious effect, 0.827
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1HNM_021098.3 linkuse as main transcriptc.2931C>G p.Asn977Lys missense_variant 14/35 ENST00000348261.11 NP_066921.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1HENST00000348261.11 linkuse as main transcriptc.2931C>G p.Asn977Lys missense_variant 14/351 NM_021098.3 ENSP00000334198 P4O95180-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152040
Hom.:
0
Cov.:
30
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:
0.00000411
AC:
6
AN:
1458114
Hom.:
0
Cov.:
33
AF XY:
0.00000414
AC XY:
3
AN XY:
725094
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152040
Hom.:
0
Cov.:
30
AF XY:
0.0000135
AC XY:
1
AN XY:
74252
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;.;.;.
Eigen
Benign
0.13
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.34
N
LIST_S2
Pathogenic
0.99
D;D;D;.
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.83
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M;.;M;M
MutationTaster
Benign
0.54
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.6
D;.;D;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0010
D;.;D;D
Sift4G
Uncertain
0.0020
D;.;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.88
MutPred
0.69
Gain of methylation at N977 (P = 0.0143);.;Gain of methylation at N977 (P = 0.0143);Gain of methylation at N977 (P = 0.0143);
MVP
0.97
ClinPred
1.0
D
GERP RS
-1.6
Varity_R
0.93
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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: rs376470846; hg19: chr16-1257298; API