rs538758039

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_021098.3(CACNA1H):​c.3425G>A​(p.Arg1142His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,547,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

5
12
2

Clinical Significance

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

Conservation

PhyloP100: 7.60
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 -5 ACMG points.

BP6
Variant 16-1209093-G-A is Benign according to our data. Variant chr16-1209093-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547866.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3425G>A p.Arg1142His 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.3425G>A p.Arg1142His missense_variant Exon 17 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.3425G>A p.Arg1142His missense_variant Exon 16 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.3386G>A p.Arg1129His missense_variant Exon 17 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000639478.1 linkn.3425G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1338G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000640028.1 linkn.*1338G>A 3_prime_UTR_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152090
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000686
AC:
10
AN:
145684
Hom.:
0
AF XY:
0.0000619
AC XY:
5
AN XY:
80734
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000266
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000471
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000511
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000222
AC:
31
AN:
1394972
Hom.:
0
Cov.:
31
AF XY:
0.0000189
AC XY:
13
AN XY:
688876
show subpopulations
Gnomad4 AFR exome
AF:
0.000160
Gnomad4 AMR exome
AF:
0.000264
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:
0.0000148
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000621
AC:
7

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 19, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3425G>A (p.R1142H) 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 3425, causing the arginine (R) at amino acid position 1142 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 Uncertain:1
Sep 06, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Mar 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
Oct 24, 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
0.33
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.61
D;.;.;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D;.
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.54
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.9
M;.;M;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-4.9
D;.;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.015
D;.;D;D
Sift4G
Uncertain
0.0020
D;.;D;D
Polyphen
1.0
D;.;D;D
Vest4
0.58
MutPred
0.23
Loss of MoRF binding (P = 0.064);.;Loss of MoRF binding (P = 0.064);Loss of MoRF binding (P = 0.064);
MVP
0.96
ClinPred
0.86
D
GERP RS
3.1
Varity_R
0.22
gMVP
0.51

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

LitVar

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

Other links and lift over

dbSNP: rs538758039; hg19: chr16-1259093; API