rs554435610

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):​c.6749G>A​(p.Arg2250His) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,609,942 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).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

4
15

Clinical Significance

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

Conservation

PhyloP100: 6.46
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0999279).
BP6
Variant 16-1220681-G-A is Benign according to our data. Variant chr16-1220681-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460178.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.6749G>A p.Arg2250His missense_variant Exon 35 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.6749G>A p.Arg2250His missense_variant Exon 35 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.6731G>A p.Arg2244His missense_variant Exon 33 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.6710G>A p.Arg2237His missense_variant Exon 35 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkc.2987G>A p.Arg996His missense_variant Exon 17 of 17 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkc.2939G>A p.Arg980His missense_variant Exon 18 of 18 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkc.2921G>A p.Arg974His missense_variant Exon 17 of 17 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000639478.1 linkn.*1797G>A non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4567G>A non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000639478.1 linkn.*1797G>A 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4567G>A 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152064
Hom.:
0
Cov.:
32
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:
0.000194
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
GnomAD3 exomes
AF:
0.00000426
AC:
1
AN:
234926
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
129080
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:
0.0000332
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1457760
Hom.:
0
Cov.:
35
AF XY:
0.00000828
AC XY:
6
AN XY:
725058
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000832
AC:
1

ClinVar

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

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Mar 01, 2022
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 Benign:1
Jul 07, 2023
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
0.087
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.48
CADD
Pathogenic
30
DANN
Uncertain
0.98
DEOGEN2
Benign
0.16
T;.;.;.
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.77
T;T;T;.
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.10
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.3
M;.;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.3
N;.;N;N
REVEL
Benign
0.056
Sift
Benign
0.031
D;.;D;D
Sift4G
Benign
0.46
T;.;T;T
Polyphen
0.0060
B;.;B;B
Vest4
0.22
MutPred
0.24
Gain of methylation at K2247 (P = 0.0498);.;.;.;
MVP
0.34
ClinPred
0.58
D
GERP RS
3.5
Varity_R
0.053
gMVP
0.23

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: rs554435610; hg19: chr16-1270681; API