NM_021098.3:c.5244+7G>A

Variant names:

• chr16-1215600-G-A
• rs2235634
• NM_021098.3:c.5244+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.5244+7G>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 0.137 in 1,608,102 control chromosomes in the GnomAD database, including 16,732 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1224 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15508 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001214
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.60
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-1215600-G-A is Benign according to our data. Variant chr16-1215600-G-A is described in ClinVar as Benign. ClinVar VariationId is 585649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5244+7G>A		splice_region intron	N/A	NP_066921.2
	CACNA1H	NM_001005407.2		c.5226+7G>A		splice_region intron	N/A	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5244+7G>A		splice_region intron	N/A	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5259+7G>A		splice_region intron	N/A	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5262+7G>A		splice_region intron	N/A	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16714 AN: 152150 Hom.: 1225 Cov.: 33

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.138 AC: 32808 AN: 238482 AF XY: 0.143

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.140 AC: 203208 AN: 1455834 Hom.: 15508 Cov.: 35 AF XY: 0.142 AC XY: 102649 AN XY: 723924

African (AFR) AF: 0.0201 AC: 670 AN: 33410

American (AMR) AF: 0.0822 AC: 3651 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5161 AN: 25976

East Asian (EAS) AF: 0.265 AC: 10477 AN: 39564

South Asian (SAS) AF: 0.174 AC: 14844 AN: 85408

European-Finnish (FIN) AF: 0.144 AC: 7401 AN: 51284

Middle Eastern (MID) AF: 0.206 AC: 1189 AN: 5764

European-Non Finnish (NFE) AF: 0.136 AC: 151003 AN: 1109830

Other (OTH) AF: 0.146 AC: 8812 AN: 60198

GnomAD4 genome AF: 0.110 AC: 16707 AN: 152268 Hom.: 1224 Cov.: 33 AF XY: 0.111 AC XY: 8252 AN XY: 74444

African (AFR) AF: 0.0247 AC: 1027 AN: 41562

American (AMR) AF: 0.0961 AC: 1470 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 693 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1205 AN: 5162

South Asian (SAS) AF: 0.182 AC: 881 AN: 4828

European-Finnish (FIN) AF: 0.141 AC: 1503 AN: 10624

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9443 AN: 68000

Other (OTH) AF: 0.126 AC: 267 AN: 2114

Alfa AF: 0.111 Hom.: 645

Bravo AF: 0.103

Asia WGS AF: 0.174 AC: 606 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.95
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
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

Other links and lift over

dbSNP: rs2235634; hg19: chr16-1265600; COSMIC: COSV61991473; COSMIC: COSV61991473;