16-1220866-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):​c.6934A>G​(p.Met2312Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,612,560 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 7 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

1
2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0470

Publications

3 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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.006071508).
BP6
Variant 16-1220866-A-G is Benign according to our data. Variant chr16-1220866-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 460180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00161 (245/152078) while in subpopulation NFE AF = 0.00184 (125/67952). AF 95% confidence interval is 0.00158. There are 3 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 245 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.6934A>G p.Met2312Val missense_variant Exon 35 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.6934A>G p.Met2312Val missense_variant Exon 35 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.6949A>G p.Met2317Val missense_variant Exon 34 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.6919A>G p.Met2307Val missense_variant Exon 34 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.6916A>G p.Met2306Val missense_variant Exon 34 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.6916A>G p.Met2306Val missense_variant Exon 35 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.6901A>G p.Met2301Val missense_variant Exon 35 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.6895A>G p.Met2299Val missense_variant Exon 35 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.6883A>G p.Met2295Val missense_variant Exon 34 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.6877A>G p.Met2293Val missense_variant Exon 34 of 34 ENSP00000518754.1
CACNA1HENST00000637236.3 linkn.*2853A>G non_coding_transcript_exon_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1982A>G non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4752A>G non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*6378A>G non_coding_transcript_exon_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1875A>G non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1793A>G non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2513A>G non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1601A>G non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1568A>G non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*848A>G non_coding_transcript_exon_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.6934A>G non_coding_transcript_exon_variant Exon 35 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.6901A>G non_coding_transcript_exon_variant Exon 35 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.*2050A>G non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000711482.1 linkc.*413A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.*413A>G 3_prime_UTR_variant Exon 35 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.*413A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.*848A>G 3_prime_UTR_variant Exon 35 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.*848A>G 3_prime_UTR_variant Exon 34 of 34 ENSP00000518769.1
CACNA1HENST00000637236.3 linkn.*2853A>G 3_prime_UTR_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1982A>G 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4752A>G 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*6378A>G 3_prime_UTR_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1875A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1793A>G 3_prime_UTR_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2513A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1601A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1568A>G 3_prime_UTR_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*848A>G 3_prime_UTR_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711488.1 linkn.*2050A>G 3_prime_UTR_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000621827.2 linkn.6121+813A>G intron_variant Intron 35 of 36 6 ENSP00000518766.1

Frequencies

GnomAD3 genomes
AF:
0.00161
AC:
245
AN:
151962
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000411
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00848
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00184
Gnomad OTH
AF:
0.00240
GnomAD2 exomes
AF:
0.00158
AC:
392
AN:
248466
AF XY:
0.00159
show subpopulations
Gnomad AFR exome
AF:
0.000195
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00835
Gnomad NFE exome
AF:
0.00166
Gnomad OTH exome
AF:
0.00215
GnomAD4 exome
AF:
0.00128
AC:
1876
AN:
1460482
Hom.:
7
Cov.:
34
AF XY:
0.00127
AC XY:
925
AN XY:
726540
show subpopulations
African (AFR)
AF:
0.000209
AC:
7
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.000536
AC:
14
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000278
AC:
24
AN:
86254
European-Finnish (FIN)
AF:
0.00978
AC:
511
AN:
52262
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5766
European-Non Finnish (NFE)
AF:
0.00111
AC:
1237
AN:
1111816
Other (OTH)
AF:
0.00133
AC:
80
AN:
60358
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
129
259
388
518
647
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
32
64
96
128
160
<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:
0.00161
AC:
245
AN:
152078
Hom.:
3
Cov.:
32
AF XY:
0.00173
AC XY:
129
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.000410
AC:
17
AN:
41484
American (AMR)
AF:
0.000327
AC:
5
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5140
South Asian (SAS)
AF:
0.000416
AC:
2
AN:
4810
European-Finnish (FIN)
AF:
0.00848
AC:
90
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00184
AC:
125
AN:
67952
Other (OTH)
AF:
0.00237
AC:
5
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
9
19
28
38
47
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00168
Hom.:
0
Bravo
AF:
0.000714
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000816
AC:
3
ESP6500EA
AF:
0.00171
AC:
14
ExAC
AF:
0.00166
AC:
201
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000927
EpiControl
AF:
0.00148

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Dec 16, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Aug 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

CACNA1H: BS1, BS2 -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Jan 23, 2025
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
0.053
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
0.0040
DANN
Benign
0.45
DEOGEN2
Benign
0.087
T;.;.;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.45
T;T;T;.
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.0061
T;T;T;T
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Benign
-0.34
N;.;.;.
PhyloP100
-0.047
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.10
N;.;N;N
REVEL
Uncertain
0.29
Sift
Benign
1.0
T;.;T;T
Sift4G
Benign
0.62
T;.;T;T
Polyphen
0.0
B;.;B;B
Vest4
0.054
MVP
0.73
ClinPred
0.0044
T
GERP RS
-6.1
Varity_R
0.10
gMVP
0.060
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs58535913; hg19: chr16-1270866; API