16-1200708-C-T

Position:

• chr16-1200708-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.1120-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,565,138 control chromosomes in the GnomAD database, including 139 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (127 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007083
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.01

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]

CACNA1H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-1200708-C-T is Benign according to our data. Variant chr16-1200708-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1200708-C-T is described in Lovd as [Benign]. Variant chr16-1200708-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00913 (1387/151962) while in subpopulation NFE AF= 0.0147 (997/68022). AF 95% confidence interval is 0.0139. There are 12 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1120-8C>T		splice_region_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.1120-8C>T		splice_region_variant, intron_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1120-8C>T		splice_region_variant, intron_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1081-8C>T		splice_region_variant, intron_variant		5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1120-8C>T		splice_region_variant, intron_variant		5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1120-8C>T		splice_region_variant, intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1388 AN: 151844 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00873 AC: 1522 AN: 174388 Hom.: 7 AF XY: 0.00918 AC XY: 860 AN XY: 93668

Gnomad AFR exome AF: 0.00268

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00183

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00742

Gnomad FIN exome AF: 0.00427

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0120 AC: 16976 AN: 1413176 Hom.: 127 Cov.: 33 AF XY: 0.0120 AC XY: 8380 AN XY: 698874

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.00716

Gnomad4 ASJ exome AF: 0.00205

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00737

Gnomad4 FIN exome AF: 0.00407

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00913 AC: 1387 AN: 151962 Hom.: 12 Cov.: 32 AF XY: 0.00859 AC XY: 638 AN XY: 74260

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00957 Hom.: 4

Bravo AF: 0.00879

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CACNA1H: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Feb 04, 2022

- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
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: rs59091981; hg19: chr16-1250708;