GeneBe

16-1220475-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_021098.3(CACNA1H):​c.6543G>T​(p.Ala2181Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,546,704 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. A2181A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.99

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: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP7
Synonymous conserved (PhyloP=-2.99 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.6543G>T p.Ala2181Ala synonymous_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.6543G>T p.Ala2181Ala synonymous_variant Exon 35 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.6558G>T p.Ala2186Ala synonymous_variant Exon 34 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.6528G>T p.Ala2176Ala synonymous_variant Exon 34 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.6525G>T p.Ala2175Ala synonymous_variant Exon 34 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.6525G>T p.Ala2175Ala synonymous_variant Exon 35 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.6510G>T p.Ala2170Ala synonymous_variant Exon 35 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.6504G>T p.Ala2168Ala synonymous_variant Exon 35 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.6492G>T p.Ala2164Ala synonymous_variant Exon 34 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.6486G>T p.Ala2162Ala synonymous_variant Exon 34 of 34 ENSP00000518754.1
CACNA1HENST00000637236.3 linkn.*2462G>T non_coding_transcript_exon_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1591G>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4361G>T non_coding_transcript_exon_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5987G>T non_coding_transcript_exon_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1484G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1402G>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2122G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1210G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1177G>T non_coding_transcript_exon_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*457G>T non_coding_transcript_exon_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.6543G>T non_coding_transcript_exon_variant Exon 35 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.6510G>T non_coding_transcript_exon_variant Exon 35 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.*1659G>T non_coding_transcript_exon_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000711482.1 linkc.*22G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.*22G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.*22G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.*457G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.*457G>T 3_prime_UTR_variant Exon 34 of 34 ENSP00000518769.1
CACNA1HENST00000637236.3 linkn.*2462G>T 3_prime_UTR_variant Exon 34 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.*1591G>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*4361G>T 3_prime_UTR_variant Exon 35 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*5987G>T 3_prime_UTR_variant Exon 33 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.*1484G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.*1402G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.*2122G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.*1210G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.*1177G>T 3_prime_UTR_variant Exon 36 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.*457G>T 3_prime_UTR_variant Exon 34 of 35 ENSP00000518773.1
CACNA1HENST00000711488.1 linkn.*1659G>T 3_prime_UTR_variant Exon 35 of 35 ENSP00000518777.1
CACNA1HENST00000621827.2 linkn.6121+422G>T intron_variant Intron 35 of 36 6 ENSP00000518766.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD4 exome
AF:
7.17e-7
AC:
1
AN:
1394566
Hom.:
0
Cov.:
35
AF XY:
0.00000145
AC XY:
1
AN XY:
689980
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000328
AC:
1
AN:
30504
American (AMR)
AF:
0.00
AC:
0
AN:
30650
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21248
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39140
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48978
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5404
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1087028
Other (OTH)
AF:
0.00
AC:
0
AN:
57366
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
0.064
DANN
Benign
0.71
PhyloP100
-3.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs117964326; hg19: chr16-1270475; API