chr16-1218044-C-T

Position:

• chr16-1218044-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.5445+4C>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 0.00391 in 1,596,214 control chromosomes in the GnomAD database, including 17 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 0.0028 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0040 (15 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005919
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.661

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=-0.77).
• BP6: Variant 16-1218044-C-T is Benign according to our data. Variant chr16-1218044-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218044-C-T is described in Lovd as [Benign]. Variant chr16-1218044-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00282 (429/152352) while in subpopulation NFE AF= 0.00465 (316/68028). AF 95% confidence interval is 0.00422. There are 2 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5445+4C>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.5445+4C>T		splice_region_variant, intron_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5427+4C>T		splice_region_variant, intron_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5406+4C>T		splice_region_variant, intron_variant		5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1683+4C>T		splice_region_variant, intron_variant		1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1668+4C>T		splice_region_variant, intron_variant		1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1650+4C>T		splice_region_variant, intron_variant		1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*526+4C>T		splice_region_variant, intron_variant		5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3296+4C>T		splice_region_variant, intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152234 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00464

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00287 AC: 640 AN: 222918 Hom.: 0 AF XY: 0.00282 AC XY: 342 AN XY: 121420

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00403 AC: 5818 AN: 1443862 Hom.: 15 Cov.: 32 AF XY: 0.00393 AC XY: 2812 AN XY: 716246

Gnomad4 AFR exome AF: 0.000724

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00500

Gnomad4 NFE exome AF: 0.00474

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152352 Hom.: 2 Cov.: 34 AF XY: 0.00258 AC XY: 192 AN XY: 74496

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.00465

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00243

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 16, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CACNA1H: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

CACNA1H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

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

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 30, 2022

- -

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	-0.77
CADD	Benign	5.2
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.028
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: rs147142971; hg19: chr16-1268044;