16-1210820-G-C

Variant summary

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

The NM_021098.3(CACNA1H):​c.4072G>C​(p.Ala1358Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 35)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.814
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, 0.884

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.4072G>C p.Ala1358Pro missense_variant Exon 21 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.4072G>C p.Ala1358Pro missense_variant Exon 21 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.4072G>C p.Ala1358Pro missense_variant Exon 20 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.4033G>C p.Ala1345Pro missense_variant Exon 21 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkc.295G>C p.Ala99Pro missense_variant Exon 4 of 17 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkc.295G>C p.Ala99Pro missense_variant Exon 4 of 18 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkc.295G>C p.Ala99Pro missense_variant Exon 4 of 17 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000637236.2 linkn.*42G>C non_coding_transcript_exon_variant Exon 5 of 6 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.4072G>C non_coding_transcript_exon_variant Exon 21 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1985G>C non_coding_transcript_exon_variant Exon 21 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000637236.2 linkn.*42G>C 3_prime_UTR_variant Exon 5 of 6 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000640028.1 linkn.*1985G>C 3_prime_UTR_variant Exon 21 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
Cov.:
35
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1450856
Hom.:
0
Cov.:
39
AF XY:
0.00000138
AC XY:
1
AN XY:
722250
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
35

ClinVar

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

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Dec 19, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1358 of the CACNA1H protein (p.Ala1358Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function with a negative predictive value of 80%. 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
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;.
Eigen
Benign
0.17
Eigen_PC
Benign
0.012
FATHMM_MKL
Benign
0.42
N
LIST_S2
Uncertain
0.97
D;D;D;.
M_CAP
Pathogenic
0.65
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M;.;M;M
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-3.7
D;.;D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.014
D;.;D;D
Sift4G
Uncertain
0.018
D;.;D;D
Polyphen
0.58
P;.;P;P
Vest4
0.72
MutPred
0.68
Gain of disorder (P = 0.0483);.;Gain of disorder (P = 0.0483);Gain of disorder (P = 0.0483);
MVP
0.98
ClinPred
0.97
D
GERP RS
2.3
Varity_R
0.53
gMVP
0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1260820; API