16-1211222-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021098.3(CACNA1H):​c.4278A>G​(p.Ser1426Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,612,144 control chromosomes in the GnomAD database, including 304,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33517 hom., cov: 34)
Exomes 𝑓: 0.61 ( 271398 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.54
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 16-1211222-A-G is Benign according to our data. Variant chr16-1211222-A-G is described in ClinVar as [Benign]. Clinvar id is 585643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1211222-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-2.54 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1HNM_021098.3 linkc.4278A>G p.Ser1426Ser synonymous_variant Exon 22 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.4278A>G p.Ser1426Ser synonymous_variant Exon 22 of 35 1 NM_021098.3 ENSP00000334198.7 O95180-1
CACNA1HENST00000565831.6 linkc.4278A>G p.Ser1426Ser synonymous_variant Exon 21 of 33 1 ENSP00000455840.1 O95180-2
CACNA1HENST00000638323.1 linkc.4239A>G p.Ser1413Ser synonymous_variant Exon 22 of 35 5 ENSP00000492267.1 A0A1W2PR14
CACNA1HENST00000569107.5 linkc.501A>G p.Ser167Ser synonymous_variant Exon 5 of 17 1 ENSP00000454990.2 H3BNT0
CACNA1HENST00000564231.5 linkc.501A>G p.Ser167Ser synonymous_variant Exon 5 of 18 1 ENSP00000457555.2 H3BUA8
CACNA1HENST00000562079.5 linkc.501A>G p.Ser167Ser synonymous_variant Exon 5 of 17 1 ENSP00000454581.2 H3BMW6
CACNA1HENST00000637236.2 linkn.*248A>G non_coding_transcript_exon_variant Exon 6 of 6 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000639478.1 linkn.4278A>G non_coding_transcript_exon_variant Exon 22 of 35 5 ENSP00000491945.1 A0A1W2PQW2
CACNA1HENST00000640028.1 linkn.*2191A>G non_coding_transcript_exon_variant Exon 22 of 35 5 ENSP00000491488.1 A0A1W2PQ19
CACNA1HENST00000637236.2 linkn.*248A>G 3_prime_UTR_variant Exon 6 of 6 5 ENSP00000492650.2 A0A1W2PS38
CACNA1HENST00000640028.1 linkn.*2191A>G 3_prime_UTR_variant Exon 22 of 35 5 ENSP00000491488.1 A0A1W2PQ19

Frequencies

GnomAD3 genomes
AF:
0.658
AC:
99933
AN:
151876
Hom.:
33488
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.733
Gnomad AMI
AF:
0.571
Gnomad AMR
AF:
0.700
Gnomad ASJ
AF:
0.706
Gnomad EAS
AF:
0.879
Gnomad SAS
AF:
0.570
Gnomad FIN
AF:
0.710
Gnomad MID
AF:
0.712
Gnomad NFE
AF:
0.583
Gnomad OTH
AF:
0.660
GnomAD3 exomes
AF:
0.652
AC:
162023
AN:
248452
Hom.:
54010
AF XY:
0.641
AC XY:
86570
AN XY:
135074
show subpopulations
Gnomad AFR exome
AF:
0.736
Gnomad AMR exome
AF:
0.739
Gnomad ASJ exome
AF:
0.690
Gnomad EAS exome
AF:
0.892
Gnomad SAS exome
AF:
0.566
Gnomad FIN exome
AF:
0.696
Gnomad NFE exome
AF:
0.588
Gnomad OTH exome
AF:
0.641
GnomAD4 exome
AF:
0.605
AC:
883958
AN:
1460150
Hom.:
271398
Cov.:
54
AF XY:
0.603
AC XY:
438145
AN XY:
726402
show subpopulations
Gnomad4 AFR exome
AF:
0.743
Gnomad4 AMR exome
AF:
0.732
Gnomad4 ASJ exome
AF:
0.692
Gnomad4 EAS exome
AF:
0.902
Gnomad4 SAS exome
AF:
0.571
Gnomad4 FIN exome
AF:
0.690
Gnomad4 NFE exome
AF:
0.581
Gnomad4 OTH exome
AF:
0.628
GnomAD4 genome
AF:
0.658
AC:
100007
AN:
151994
Hom.:
33517
Cov.:
34
AF XY:
0.665
AC XY:
49444
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.732
Gnomad4 AMR
AF:
0.700
Gnomad4 ASJ
AF:
0.706
Gnomad4 EAS
AF:
0.878
Gnomad4 SAS
AF:
0.569
Gnomad4 FIN
AF:
0.710
Gnomad4 NFE
AF:
0.583
Gnomad4 OTH
AF:
0.665
Alfa
AF:
0.606
Hom.:
35187
Bravo
AF:
0.667
Asia WGS
AF:
0.730
AC:
2537
AN:
3478
EpiCase
AF:
0.599
EpiControl
AF:
0.588

ClinVar

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

Submissions by phenotype

not provided Benign:3
Apr 20, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jan 16, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: 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
-0.88
CADD
Benign
0.073
DANN
Benign
0.53

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: rs2753325; hg19: chr16-1261222; COSMIC: COSV61998716; COSMIC: COSV61998716; API