rs754398374

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_021098.3(CACNA1H):​c.6617C>T​(p.Pro2206Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,531,918 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
7
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.46
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.27028102).
BP6
Variant 16-1220549-C-T is Benign according to our data. Variant chr16-1220549-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 581895.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1HNM_021098.3 linkuse as main transcriptc.6617C>T p.Pro2206Leu missense_variant 35/35 ENST00000348261.11 NP_066921.2 O95180-1B3KQH9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1HENST00000348261.11 linkuse as main transcriptc.6617C>T p.Pro2206Leu missense_variant 35/351 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkuse as main transcriptc.6599C>T p.Pro2200Leu missense_variant 33/331 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkuse as main transcriptc.6578C>T p.Pro2193Leu missense_variant 35/355 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkuse as main transcriptc.2855C>T p.Pro952Leu missense_variant 17/171 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkuse as main transcriptc.2807C>T p.Pro936Leu missense_variant 18/181 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkuse as main transcriptc.2789C>T p.Pro930Leu missense_variant 17/171 ENSP00000454581.2 H3BMW6
CACNA1HENST00000639478.1 linkuse as main transcriptn.*1665C>T non_coding_transcript_exon_variant 35/355 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkuse as main transcriptn.*4435C>T non_coding_transcript_exon_variant 35/355 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000639478.1 linkuse as main transcriptn.*1665C>T 3_prime_UTR_variant 35/355 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkuse as main transcriptn.*4435C>T 3_prime_UTR_variant 35/355 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151984
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000595
AC:
1
AN:
168062
Hom.:
0
AF XY:
0.0000109
AC XY:
1
AN XY:
91810
show subpopulations
Gnomad AFR exome
AF:
0.0000768
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000290
AC:
4
AN:
1379934
Hom.:
0
Cov.:
35
AF XY:
0.00000441
AC XY:
3
AN XY:
680044
show subpopulations
Gnomad4 AFR exome
AF:
0.000132
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151984
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74226
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.00000855
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 03, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 02, 2020Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 -
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T;.;.;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.33
N
LIST_S2
Benign
0.77
T;T;T;.
M_CAP
Pathogenic
0.59
D
MetaRNN
Benign
0.27
T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.7
M;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-4.0
D;.;D;D
REVEL
Benign
0.097
Sift
Uncertain
0.0020
D;.;D;D
Sift4G
Uncertain
0.0050
D;.;D;D
Polyphen
0.0060
B;.;B;B
Vest4
0.23
MutPred
0.21
Loss of glycosylation at S2203 (P = 0.0607);.;.;.;
MVP
0.52
ClinPred
0.71
D
GERP RS
3.7
Varity_R
0.34
gMVP
0.090

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: rs754398374; hg19: chr16-1270549; COSMIC: COSV52354892; COSMIC: COSV52354892; API