16-1216940-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):​c.5253C>T​(p.Asn1751Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,602,734 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 34)
Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 2.49
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 16-1216940-C-T is Benign according to our data. Variant chr16-1216940-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=2.49 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00174 (265/152316) while in subpopulation NFE AF= 0.00316 (215/68010). AF 95% confidence interval is 0.00281. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High AC in GnomAd4 at 265 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.5253C>T p.Asn1751Asn synonymous_variant Exon 31 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.5253C>T p.Asn1751Asn synonymous_variant Exon 31 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.5235C>T p.Asn1745Asn synonymous_variant Exon 29 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.5214C>T p.Asn1738Asn synonymous_variant Exon 31 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkc.1491C>T p.Asn497Asn synonymous_variant Exon 13 of 17 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkc.1476C>T p.Asn492Asn synonymous_variant Exon 14 of 18 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkc.1458C>T p.Asn486Asn synonymous_variant Exon 13 of 17 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000639478.1 linkn.*334C>T non_coding_transcript_exon_variant Exon 31 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*3104C>T non_coding_transcript_exon_variant Exon 31 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000639478.1 linkn.*334C>T 3_prime_UTR_variant Exon 31 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*3104C>T 3_prime_UTR_variant Exon 31 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.00174
AC:
265
AN:
152198
Hom.:
1
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000851
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00316
Gnomad OTH
AF:
0.00334
GnomAD3 exomes
AF:
0.00170
AC:
384
AN:
226014
Hom.:
1
AF XY:
0.00178
AC XY:
219
AN XY:
123084
show subpopulations
Gnomad AFR exome
AF:
0.000296
Gnomad AMR exome
AF:
0.000868
Gnomad ASJ exome
AF:
0.000731
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00215
Gnomad FIN exome
AF:
0.000247
Gnomad NFE exome
AF:
0.00260
Gnomad OTH exome
AF:
0.00354
GnomAD4 exome
AF:
0.00213
AC:
3084
AN:
1450418
Hom.:
9
Cov.:
31
AF XY:
0.00216
AC XY:
1559
AN XY:
720420
show subpopulations
Gnomad4 AFR exome
AF:
0.000330
Gnomad4 AMR exome
AF:
0.000838
Gnomad4 ASJ exome
AF:
0.000425
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00226
Gnomad4 FIN exome
AF:
0.000344
Gnomad4 NFE exome
AF:
0.00242
Gnomad4 OTH exome
AF:
0.00198
GnomAD4 genome
AF:
0.00174
AC:
265
AN:
152316
Hom.:
1
Cov.:
34
AF XY:
0.00165
AC XY:
123
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000849
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.00316
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00153
Hom.:
0
Bravo
AF:
0.00157
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

CACNA1H-related disorder Benign:1
Oct 11, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Oct 14, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CACNA1H: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.44
CADD
Benign
12
DANN
Benign
0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs57181695; hg19: chr16-1266940; COSMIC: COSV99326294; COSMIC: COSV99326294; API