rs202115678

Variant names:

• chr16-1210578-G-A
• rs202115678
• NM_021098.3:c.3970-5G>A

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.3970-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,609,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.007016
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.397

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=-0.83).
• BP6: Variant 16-1210578-G-A is Benign according to our data. Variant chr16-1210578-G-A is described in ClinVar as [Benign]. Clinvar id is 460102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000342 (52/152254) while in subpopulation EAS AF= 0.00174 (9/5182). AF 95% confidence interval is 0.000906. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3970-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3970-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3970-5G>A		splice_region_variant, intron_variant	Intron 18 of 32	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3931-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.193-5G>A		splice_region_variant, intron_variant	Intron 2 of 16	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.193-5G>A		splice_region_variant, intron_variant	Intron 2 of 17	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.193-5G>A		splice_region_variant, intron_variant	Intron 2 of 16	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.333-5G>A		splice_region_variant, intron_variant	Intron 3 of 5	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3970-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1883-5G>A		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000253 AC: 62 AN: 244720 Hom.: 0 AF XY: 0.000299 AC XY: 40 AN XY: 133642

Gnomad AFR exome AF: 0.000657

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00268

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000520

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000968 AC: 141 AN: 1457014 Hom.: 0 Cov.: 40 AF XY: 0.0000993 AC XY: 72 AN XY: 724898

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74438

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000397

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0070
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202115678; hg19: chr16-1260578;