NM_021098.3:c.6440C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_021098.3(CACNA1H):​c.6440C>T​(p.Pro2147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,522,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2147Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

5
10
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.44

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: Likely_benign. The variant received -5 ACMG points.

BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/152194) while in subpopulation AMR AF = 0.000785 (12/15290). AF 95% confidence interval is 0.000452. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.6440C>T p.Pro2147Leu 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.6440C>T p.Pro2147Leu missense_variant Exon 35 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.6455C>T p.Pro2152Leu missense_variant Exon 34 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.6425C>T p.Pro2142Leu missense_variant Exon 34 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.6422C>T p.Pro2141Leu missense_variant Exon 34 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.6422C>T p.Pro2141Leu missense_variant Exon 35 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.6407C>T p.Pro2136Leu missense_variant Exon 35 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.6401C>T p.Pro2134Leu missense_variant Exon 35 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.6389C>T p.Pro2130Leu missense_variant Exon 34 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.6383C>T p.Pro2128Leu missense_variant Exon 34 of 34 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.6333C>T p.Ala2111Ala synonymous_variant Exon 36 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.6282C>T p.Ala2094Ala synonymous_variant Exon 35 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.6255C>T p.Ala2085Ala synonymous_variant Exon 36 of 36 ENSP00000518768.1
CACNA1HENST00000637236.3 linkn.*2359C>T non_coding_transcript_exon_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1488C>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4258C>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5884C>T non_coding_transcript_exon_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1381C>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1299C>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2019C>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1107C>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1074C>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*354C>T non_coding_transcript_exon_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.6440C>T non_coding_transcript_exon_variant Exon 35 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.6407C>T non_coding_transcript_exon_variant Exon 35 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.*1556C>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000711483.1 linkc.*354C>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.*354C>T 3_prime_UTR_variant Exon 34 of 34 ENSP00000518769.1
CACNA1HENST00000637236.3 linkn.*2359C>T 3_prime_UTR_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1488C>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4258C>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5884C>T 3_prime_UTR_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1381C>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1299C>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2019C>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1107C>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1074C>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*354C>T 3_prime_UTR_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711488.1 linkn.*1556C>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000621827.2 linkn.6121+319C>T intron_variant Intron 35 of 36 6 ENSP00000518766.1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
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:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000522
AC:
8
AN:
153156
AF XY:
0.0000349
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000828
Gnomad NFE exome
AF:
0.0000812
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000482
AC:
66
AN:
1370052
Hom.:
0
Cov.:
35
AF XY:
0.0000429
AC XY:
29
AN XY:
675736
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28860
American (AMR)
AF:
0.0000665
AC:
2
AN:
30078
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
20742
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37140
South Asian (SAS)
AF:
0.0000136
AC:
1
AN:
73364
European-Finnish (FIN)
AF:
0.000117
AC:
5
AN:
42614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5348
European-Non Finnish (NFE)
AF:
0.0000530
AC:
57
AN:
1075492
Other (OTH)
AF:
0.0000177
AC:
1
AN:
56414
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
5
10
14
19
24
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:
0.000118
AC:
18
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74354
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41450
American (AMR)
AF:
0.000785
AC:
12
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68016
Other (OTH)
AF:
0.000478
AC:
1
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
2
4
5
6
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:
0.0000712
Hom.:
0
Bravo
AF:
0.000170
ExAC
AF:
0.0000877
AC:
10

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Sep 30, 2024
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign. -

Oct 03, 2016
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The P2147L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. The P2147L variant is a semi-conservative amino acid substitution that occurs at a position in the predicted cytoplasmic domain that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified Uncertain:1
Feb 12, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CACNA1H c.6440C>T (p.Pro2147Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 153156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6440C>T in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 389769). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1
Nov 09, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.6440C>T (p.P2147L) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 6440, causing the proline (P) at amino acid position 2147 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Jun 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Uncertain
0.050
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;.;.
Eigen
Benign
0.023
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.89
D;D;D;.
M_CAP
Pathogenic
0.93
D
MetaRNN
Uncertain
0.46
T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
2.9
M;.;.;.
PhyloP100
2.4
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-5.9
D;.;D;D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0010
D;.;D;D
Sift4G
Pathogenic
0.0010
D;.;D;D
Polyphen
0.45
B;.;D;D
Vest4
0.23
MutPred
0.30
Loss of ubiquitination at K2146 (P = 0.0369);.;.;.;
MVP
0.95
ClinPred
0.49
T
GERP RS
4.4
Varity_R
0.24
gMVP
0.26
Mutation Taster
=66/34
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: rs748980218; hg19: chr16-1270372; API