rs2235634

chr16-1215600-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):c.5244+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,608,102 control chromosomes in the GnomAD database, including 16,732 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1224 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15508 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001214
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.60

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-1215600-G-A is Benign according to our data. Variant chr16-1215600-G-A is described in ClinVar as [Benign]. Clinvar id is 585649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1215600-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5244+7G>A		splice_region_variant, intron_variant		ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5244+7G>A		splice_region_variant, intron_variant		1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16714 AN: 152150 Hom.: 1225 Cov.: 33

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.138 AC: 32808 AN: 238482 Hom.: 2557 AF XY: 0.143 AC XY: 18635 AN XY: 130216

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.140 AC: 203208 AN: 1455834 Hom.: 15508 Cov.: 35 AF XY: 0.142 AC XY: 102649 AN XY: 723924

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.0822

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.110 AC: 16707 AN: 152268 Hom.: 1224 Cov.: 33 AF XY: 0.111 AC XY: 8252 AN XY: 74444

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.0961

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.126

Alfa AF: 0.126 Hom.: 638

Bravo AF: 0.103

Asia WGS AF: 0.174 AC: 606 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.1
Dann	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs2235634; hg19: chr16-1265600; COSMIC: COSV61991473; COSMIC: COSV61991473;