rs58615599

Positions:

• chr16-1207092-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.2881C>T​(p.Leu961=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00779 in 1,598,686 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0080 (60 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.91

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-1207092-C-T is Benign according to our data. Variant chr16-1207092-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1207092-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00588 (894/152144) while in subpopulation NFE AF= 0.0105 (711/67968). AF 95% confidence interval is 0.00982. There are 7 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2881C>T	p.Leu961=	synonymous_variant	13/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2881C>T	p.Leu961=	synonymous_variant	13/35	1	NM_021098.3	ENSP00000334198	P4
	ENST00000564700.1	n.33G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 894 AN: 152026 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00475 AC: 1067 AN: 224732 Hom.: 2 AF XY: 0.00494 AC XY: 601 AN XY: 121626

Gnomad AFR exome AF: 0.00128

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.000732

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00808

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00799 AC: 11560 AN: 1446542 Hom.: 60 Cov.: 32 AF XY: 0.00797 AC XY: 5720 AN XY: 717994

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.000967

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.00595

GnomAD4 genome AF: 0.00588 AC: 894 AN: 152144 Hom.: 7 Cov.: 30 AF XY: 0.00554 AC XY: 412 AN XY: 74368

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00817 Hom.: 3

Bravo AF: 0.00535

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1H: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

CACNA1H-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

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

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs58615599; hg19: chr16-1257092;