rs191783113

Positions:

• chr16-1206099-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000348261.11(CACNA1H):​c.2604-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,566,408 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: CACNA1H ENST00000348261.11 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002266
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.119

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-1206099-C-T is Benign according to our data. Variant chr16-1206099-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2604-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2604-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000248 AC: 46 AN: 185538 Hom.: 0 AF XY: 0.000248 AC XY: 25 AN XY: 100882

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000275

Gnomad ASJ exome AF: 0.000787

Gnomad EAS exome AF: 0.000143

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000190 AC: 269 AN: 1414072 Hom.: 0 Cov.: 31 AF XY: 0.000189 AC XY: 132 AN XY: 699580

Gnomad4 AFR exome AF: 0.0000921

Gnomad4 AMR exome AF: 0.000300

Gnomad4 ASJ exome AF: 0.000711

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.000689

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000324

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74488

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1H: BP4 -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs191783113; hg19: chr16-1256099;