chr16-1210813-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_021098.3(CACNA1H):​c.4065C>T​(p.Gly1355Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000325 in 1,602,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.147

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 -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 16-1210813-C-T is Benign according to our data. Variant chr16-1210813-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460109.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BP7
Synonymous conserved (PhyloP=0.147 with no splicing effect.
BS2
High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 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.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000569107.6 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 34 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000711493.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 34 ENSP00000518778.1
CACNA1HENST00000565831.7 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 34 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000711450.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 35 ENSP00000518762.1
CACNA1HENST00000564231.6 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 35 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000638323.1 linkc.4026C>T p.Gly1342Gly synonymous_variant Exon 21 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000562079.6 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 34 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000711438.1 linkc.4026C>T p.Gly1342Gly synonymous_variant Exon 21 of 34 ENSP00000518754.1
CACNA1HENST00000711482.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 36 ENSP00000518771.1
CACNA1HENST00000711485.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 35 ENSP00000518774.1
CACNA1HENST00000711455.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 36 ENSP00000518768.1
CACNA1HENST00000711483.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 35 ENSP00000518772.1
CACNA1HENST00000711456.1 linkc.4065C>T p.Gly1355Gly synonymous_variant Exon 21 of 34 ENSP00000518769.1
CACNA1HENST00000621827.2 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 37 6 ENSP00000518766.1
CACNA1HENST00000637236.3 linkn.*35C>T non_coding_transcript_exon_variant Exon 21 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*1978C>T non_coding_transcript_exon_variant Exon 21 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3512C>T non_coding_transcript_exon_variant Exon 20 of 34 ENSP00000518758.1
CACNA1HENST00000711448.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 36 ENSP00000518760.1
CACNA1HENST00000711449.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 35 ENSP00000518761.1
CACNA1HENST00000711451.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 36 ENSP00000518763.1
CACNA1HENST00000711452.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 36 ENSP00000518764.1
CACNA1HENST00000711453.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 36 ENSP00000518765.1
CACNA1HENST00000711484.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 35 ENSP00000518773.1
CACNA1HENST00000711486.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 37 ENSP00000518775.1
CACNA1HENST00000711487.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 36 ENSP00000518776.1
CACNA1HENST00000711488.1 linkn.4065C>T non_coding_transcript_exon_variant Exon 21 of 35 ENSP00000518777.1
CACNA1HENST00000637236.3 linkn.*35C>T 3_prime_UTR_variant Exon 21 of 34 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000640028.1 linkn.*1978C>T 3_prime_UTR_variant Exon 21 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000711442.1 linkn.*3512C>T 3_prime_UTR_variant Exon 20 of 34 ENSP00000518758.1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152260
Hom.:
0
Cov.:
35
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:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000626
AC:
15
AN:
239758
AF XY:
0.0000837
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:
0.000548
Gnomad NFE exome
AF:
0.0000450
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000338
AC:
49
AN:
1450154
Hom.:
0
Cov.:
39
AF XY:
0.0000305
AC XY:
22
AN XY:
721956
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33466
American (AMR)
AF:
0.0000224
AC:
1
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26110
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86244
European-Finnish (FIN)
AF:
0.000804
AC:
34
AN:
42294
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5718
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1111666
Other (OTH)
AF:
0.0000498
AC:
3
AN:
60270
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
5
10
15
20
25
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:
152260
Hom.:
0
Cov.:
35
AF XY:
0.0000134
AC XY:
1
AN XY:
74396
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000241
AC:
1
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.0000941
AC:
1
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68048
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.001943), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.358
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

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:
0.00
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jul 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Jul 06, 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
BayesDel_noAF
Benign
-0.46
CADD
Benign
1.2
DANN
Benign
0.51
PhyloP100
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs771718484; hg19: chr16-1260813; COSMIC: COSV100671292; COSMIC: COSV100671292; API