NM_021098.3:c.3650G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_021098.3(CACNA1H):​c.3650G>A​(p.Arg1217His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,597,748 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1217C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.46
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28671065).
BP6
Variant 16-1209318-G-A is Benign according to our data. Variant chr16-1209318-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529608.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3650G>A p.Arg1217His 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.3650G>A p.Arg1217His missense_variant Exon 17 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.3650G>A p.Arg1217His missense_variant Exon 16 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.3611G>A p.Arg1204His missense_variant Exon 17 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000639478.1 linkn.3650G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1563G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000640028.1 linkn.*1563G>A 3_prime_UTR_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000637236.2 linkn.-38G>A upstream_gene_variant 5 ENSP00000492650.2 A0A1W2PS38

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000289
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000176
AC:
4
AN:
227338
Hom.:
0
AF XY:
0.0000158
AC XY:
2
AN XY:
126212
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000287
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000214
AC:
31
AN:
1445418
Hom.:
0
Cov.:
31
AF XY:
0.0000195
AC XY:
14
AN XY:
719486
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000313
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000117
ESP6500AA
AF:
0.000502
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000256
AC:
3
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3650G>A (p.R1217H) alteration is located in exon 17 (coding exon 16) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 3650, causing the arginine (R) at amino acid position 1217 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Jun 11, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Apr 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.081
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
T;.;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.74
T;T;T;.
M_CAP
Pathogenic
0.63
D
MetaRNN
Benign
0.29
T;T;T;T
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
0.0
N;.;N;N
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.80
N;.;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.086
T;.;T;T
Sift4G
Benign
0.13
T;.;T;T
Polyphen
0.96
D;.;D;D
Vest4
0.33
MVP
0.79
ClinPred
0.18
T
GERP RS
3.2
Varity_R
0.075
gMVP
0.55

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: rs374847612; hg19: chr16-1259318; API