rs1555515661

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021098.3(CACNA1H):​c.3599A>C​(p.Asp1200Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,314 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
9
9

Clinical Significance

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

Conservation

PhyloP100: 3.27
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40273336).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3599A>C p.Asp1200Ala 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.3599A>C p.Asp1200Ala missense_variant Exon 17 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.3599A>C p.Asp1200Ala missense_variant Exon 16 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.3560A>C p.Asp1187Ala missense_variant Exon 17 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000639478.1 linkn.3599A>C non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1512A>C non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000640028.1 linkn.*1512A>C 3_prime_UTR_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000637236.2 linkn.-89A>C upstream_gene_variant 5 ENSP00000492650.2 A0A1W2PS38

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.14e-7
AC:
1
AN:
1400314
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
692546
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000276
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

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 Uncertain:1
Jun 04, 2018
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Sep 03, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid with alanine at codon 1200 of the CACNA1H protein (p.Asp1200Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CACNA1H-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
0.18
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
19
DANN
Benign
0.90
DEOGEN2
Uncertain
0.52
D;.;.;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.47
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.76
T;T;T;.
M_CAP
Pathogenic
0.48
D
MetaRNN
Benign
0.40
T;T;T;T
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.7
M;.;M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.8
D;.;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.011
D;.;D;D
Sift4G
Benign
0.075
T;.;T;T
Polyphen
0.0040
B;.;B;B
Vest4
0.38
MutPred
0.30
Gain of MoRF binding (P = 0.0326);.;Gain of MoRF binding (P = 0.0326);Gain of MoRF binding (P = 0.0326);
MVP
0.88
ClinPred
0.77
D
GERP RS
1.4
Varity_R
0.16
gMVP
0.64

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: rs1555515661; hg19: chr16-1259267; API