16-1209227-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):​c.3559G>A​(p.Gly1187Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,544,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1187G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
4
14

Clinical Significance

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

Conservation

PhyloP100: 1.13

Publications

0 publications found
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]
CACNA1H Gene-Disease associations (from GenCC):
  • hyperaldosteronism, familial, type IV
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • childhood absence epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • epilepsy, childhood absence, susceptibility to, 6
    Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20753449).
BP6
Variant 16-1209227-G-A is Benign according to our data. Variant chr16-1209227-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460088.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 66 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.3559G>A p.Gly1187Arg 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.3559G>A p.Gly1187Arg missense_variant Exon 17 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.3520G>A p.Gly1174Arg missense_variant Exon 17 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.3520G>A p.Gly1174Arg missense_variant Exon 17 of 34 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.3559G>A p.Gly1187Arg missense_variant Exon 17 of 34 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 37 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1472G>A non_coding_transcript_exon_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3006G>A non_coding_transcript_exon_variant Exon 16 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.3559G>A non_coding_transcript_exon_variant Exon 17 of 35 ENSP00000518777.1
CACNA1HENST00000640028.1 linkn.*1472G>A 3_prime_UTR_variant Exon 17 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3006G>A 3_prime_UTR_variant Exon 16 of 34 ENSP00000518758.1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152144
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000874
AC:
12
AN:
137228
AF XY:
0.0000664
show subpopulations
Gnomad AFR exome
AF:
0.000182
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000390
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000474
AC:
66
AN:
1392420
Hom.:
0
Cov.:
31
AF XY:
0.0000538
AC XY:
37
AN XY:
687258
show subpopulations
African (AFR)
AF:
0.0000970
AC:
3
AN:
30928
American (AMR)
AF:
0.0000280
AC:
1
AN:
35730
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24996
East Asian (EAS)
AF:
0.0000282
AC:
1
AN:
35402
South Asian (SAS)
AF:
0.000354
AC:
28
AN:
78986
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
44364
Middle Eastern (MID)
AF:
0.000176
AC:
1
AN:
5678
European-Non Finnish (NFE)
AF:
0.0000250
AC:
27
AN:
1078510
Other (OTH)
AF:
0.0000865
AC:
5
AN:
57826
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74438
show subpopulations
African (AFR)
AF:
0.0000240
AC:
1
AN:
41580
American (AMR)
AF:
0.00
AC:
0
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00342
AC:
1
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67982
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000383
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000699
AC:
7
Asia WGS
AF:
0.000289
AC:
1
AN:
3470

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 05, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3559G>A (p.G1187R) alteration is located in exon 17 (coding exon 16) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 3559, causing the glycine (G) at amino acid position 1187 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Jan 24, 2024
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
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
11
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
T;.;.;.
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.54
T;T;T;.
M_CAP
Pathogenic
0.89
D
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Uncertain
0.022
D
MutationAssessor
Uncertain
2.3
M;.;M;M
PhyloP100
1.1
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.61
N;.;N;N
REVEL
Benign
0.27
Sift
Benign
0.19
T;.;T;T
Sift4G
Benign
0.17
T;.;T;T
Polyphen
0.83
P;.;P;P
Vest4
0.19
MutPred
0.28
Gain of MoRF binding (P = 0.0169);.;Gain of MoRF binding (P = 0.0169);Gain of MoRF binding (P = 0.0169);
MVP
0.69
ClinPred
0.029
T
GERP RS
3.0
Varity_R
0.078
gMVP
0.44
Mutation Taster
=89/11
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs772258959; hg19: chr16-1259227; API