rs543267343

chr16-1208009-G-Achr16-1208009-G-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.3155-4G>A 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 0.000065 in 1,598,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001810
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.460

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-1208009-G-A is Benign according to our data. Variant chr16-1208009-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152224) while in subpopulation AMR AF= 0.000588 (9/15302). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3155-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3155-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000932 AC: 21 AN: 225370 Hom.: 0 AF XY: 0.000131 AC XY: 16 AN XY: 122422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000254

Gnomad FIN exome AF: 0.0000500

Gnomad NFE exome AF: 0.0000696

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 91 AN: 1446748 Hom.: 0 Cov.: 33 AF XY: 0.0000696 AC XY: 50 AN XY: 718302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000323

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000398

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74416

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000125

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 03, 2022

- -

CACNA1H-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 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). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.2
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
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: rs543267343; hg19: chr16-1258009;