rs200403676

Positions:

• chr16-1210577-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.3970-6C>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 0.000114 in 1,609,406 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.214

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=-0.82).
• BP6: Variant 16-1210577-C-T is Benign according to our data. Variant chr16-1210577-C-T is described in ClinVar as [Benign]. Clinvar id is 460103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000499 (76/152308) while in subpopulation AFR AF= 0.00164 (68/41568). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3970-6C>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.3970-6C>T		splice_region_variant, intron_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3970-6C>T		splice_region_variant, intron_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3931-6C>T		splice_region_variant, intron_variant		5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.193-6C>T		splice_region_variant, intron_variant		1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.193-6C>T		splice_region_variant, intron_variant		1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.193-6C>T		splice_region_variant, intron_variant		1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.333-6C>T		splice_region_variant, intron_variant		5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3970-6C>T		splice_region_variant, intron_variant		5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1883-6C>T		splice_region_variant, intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000188 AC: 46 AN: 244716 Hom.: 0 AF XY: 0.000112 AC XY: 15 AN XY: 133668

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000741 AC: 108 AN: 1457098 Hom.: 0 Cov.: 40 AF XY: 0.0000800 AC XY: 58 AN XY: 724962

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74478

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000635

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 16, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs200403676; hg19: chr16-1260577;