GeneBe

rs72552061

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000711450.1(CACNA1H):​c.4788C>A​(p.Pro1596Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1596P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
ENST00000711450.1 synonymous

Scores

2
Splicing: ADA: 0.9723
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.22

Publications

2 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: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 34 ENST00000348261.11 NP_066921.2 O95180-1B3KQH9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1HENST00000711450.1 linkc.4788C>A p.Pro1596Pro synonymous_variant Exon 27 of 35 ENSP00000518762.1
CACNA1HENST00000711442.1 linkn.*4217C>A non_coding_transcript_exon_variant Exon 25 of 34 ENSP00000518758.1
CACNA1HENST00000711451.1 linkn.4850C>A non_coding_transcript_exon_variant Exon 27 of 36 ENSP00000518763.1
CACNA1HENST00000711488.1 linkn.4832C>A non_coding_transcript_exon_variant Exon 26 of 35 ENSP00000518777.1
CACNA1HENST00000711442.1 linkn.*4217C>A 3_prime_UTR_variant Exon 25 of 34 ENSP00000518758.1
CACNA1HENST00000348261.11 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 34 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.4793-5C>A splice_region_variant, intron_variant Intron 25 of 33 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.4796-5C>A splice_region_variant, intron_variant Intron 25 of 33 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.4760-5C>A splice_region_variant, intron_variant Intron 25 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000564231.6 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 34 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.4739-5C>A splice_region_variant, intron_variant Intron 26 of 34 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.4760-5C>A splice_region_variant, intron_variant Intron 25 of 33 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.4721-5C>A splice_region_variant, intron_variant Intron 25 of 33 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 35 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.4760-5C>A splice_region_variant, intron_variant Intron 25 of 34 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 35 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 34 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.4778-5C>A splice_region_variant, intron_variant Intron 26 of 33 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.4778-5C>A splice_region_variant, intron_variant Intron 26 of 36 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.*730-5C>A splice_region_variant, intron_variant Intron 25 of 33 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.4716-5C>A splice_region_variant, intron_variant Intron 26 of 34 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*2629-5C>A splice_region_variant, intron_variant Intron 26 of 34 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711448.1 linkn.4760-5C>A splice_region_variant, intron_variant Intron 25 of 35 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.4760-5C>A splice_region_variant, intron_variant Intron 25 of 34 ENSP00000518761.1
CACNA1HENST00000711452.1 linkn.4778-5C>A splice_region_variant, intron_variant Intron 26 of 35 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.4778-5C>A splice_region_variant, intron_variant Intron 26 of 35 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.4760-5C>A splice_region_variant, intron_variant Intron 25 of 34 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.4778-5C>A splice_region_variant, intron_variant Intron 26 of 36 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.4778-5C>A splice_region_variant, intron_variant Intron 26 of 35 ENSP00000518776.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000128
AC:
2
AN:
155958
AF XY:
0.0000119
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:
0.0000884
Gnomad NFE exome
AF:
0.0000158
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000143
AC:
2
AN:
1395590
Hom.:
0
Cov.:
31
AF XY:
0.00000145
AC XY:
1
AN XY:
688868
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31790
American (AMR)
AF:
0.00
AC:
0
AN:
35968
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25182
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36242
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79674
European-Finnish (FIN)
AF:
0.0000236
AC:
1
AN:
42312
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5548
European-Non Finnish (NFE)
AF:
9.25e-7
AC:
1
AN:
1080798
Other (OTH)
AF:
0.00
AC:
0
AN:
58076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
11
DANN
Benign
0.82
PhyloP100
-2.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Pathogenic
0.81
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.40
Position offset: 2
DS_AL_spliceai
0.42
Position offset: 5

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

Publications

Other links and lift over

dbSNP: rs72552061; hg19: chr16-1263775; API