16-1215066-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021098.3(CACNA1H):​c.5024G>T​(p.Arg1675Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1H
NM_021098.3 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.5024G>T p.Arg1675Leu missense_variant Exon 28 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.5024G>T p.Arg1675Leu missense_variant Exon 28 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.5006G>T p.Arg1669Leu missense_variant Exon 26 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.4985G>T p.Arg1662Leu missense_variant Exon 28 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkc.1262G>T p.Arg421Leu missense_variant Exon 10 of 17 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkc.1247G>T p.Arg416Leu missense_variant Exon 11 of 18 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkc.1229G>T p.Arg410Leu missense_variant Exon 10 of 17 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000639478.1 linkn.*105G>T non_coding_transcript_exon_variant Exon 28 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*2875G>T non_coding_transcript_exon_variant Exon 28 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000639478.1 linkn.*105G>T 3_prime_UTR_variant Exon 28 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*2875G>T 3_prime_UTR_variant Exon 28 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 13, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D;D;.
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.8
L;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.9
D;.;D;D
REVEL
Pathogenic
0.86
Sift
Benign
0.11
T;.;T;T
Sift4G
Benign
0.16
T;.;T;T
Polyphen
0.98
D;.;D;D
Vest4
0.86
MutPred
0.64
Loss of MoRF binding (P = 0.0269);.;.;.;
MVP
0.98
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.70
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1265066; API