rs1258785345

Variant names:

• chr16-1218659-A-G
• rs1258785345
• NM_021098.3:c.5887+8A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021098.3(CACNA1H):​c.5887+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,374,726 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001963
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.740
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-1218659-A-G is Benign according to our data. Variant chr16-1218659-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 460155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.5902+8A>G		splice_region_variant, intron_variant	Intron 32 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.5905+8A>G		splice_region_variant, intron_variant	Intron 32 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.5869+8A>G		splice_region_variant, intron_variant	Intron 32 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.5902+8A>G		splice_region_variant, intron_variant	Intron 33 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.5848+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.5869+8A>G		splice_region_variant, intron_variant	Intron 32 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.5830+8A>G		splice_region_variant, intron_variant	Intron 32 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.5869+8A>G		splice_region_variant, intron_variant	Intron 32 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*1839+8A>G		splice_region_variant, intron_variant	Intron 32 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*968+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3738+8A>G		splice_region_variant, intron_variant	Intron 33 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5331+8A>G		splice_region_variant, intron_variant	Intron 31 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*861+8A>G		splice_region_variant, intron_variant	Intron 34 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*746+8A>G		splice_region_variant, intron_variant	Intron 33 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1499+8A>G		splice_region_variant, intron_variant	Intron 34 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*554+8A>G		splice_region_variant, intron_variant	Intron 34 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*554+8A>G		splice_region_variant, intron_variant	Intron 34 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.5869+8A>G		splice_region_variant, intron_variant	Intron 32 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.5887+8A>G		splice_region_variant, intron_variant	Intron 33 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1003+8A>G		splice_region_variant, intron_variant	Intron 33 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000716 AC: 1 AN: 139742 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 21 AN: 1374726 Hom.: 0 Cov.: 38 AF XY: 0.0000163 AC XY: 11 AN XY: 674626

African (AFR) AF: 0.00 AC: 0 AN: 31508

American (AMR) AF: 0.00 AC: 0 AN: 34646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23302

East Asian (EAS) AF: 0.00 AC: 0 AN: 36072

South Asian (SAS) AF: 0.00 AC: 0 AN: 75410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.0000160 AC: 17 AN: 1064982

Other (OTH) AF: 0.0000705 AC: 4 AN: 56772

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	0.90
DANN	Benign	0.34
PhyloP100		-0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1258785345; hg19: chr16-1268659;