rs28365116

Variant names:

• chr16-1204375-G-A
• rs28365116
• NM_021098.3:c.2368G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP3 BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000569107.6(CACNA1H):​c.2368G>A​(p.Val790Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,567,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: CACNA1H ENST00000569107.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.83
• Publications: 7 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 -17 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.13133818).
• BP6: Variant 16-1204375-G-A is Benign according to our data. Variant chr16-1204375-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 585634.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 = 0.000663 (101/152344) while in subpopulation AFR AF = 0.00207 (86/41576). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 101 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000569107.6. 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.2368G>A	p.Val790Met	missense	Exon 10 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.2368G>A	p.Val790Met	missense	Exon 10 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.2368G>A	p.Val790Met	missense	Exon 10 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.2368G>A	p.Val790Met	missense	Exon 10 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.2368G>A	p.Val790Met	missense	Exon 10 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000211 AC: 44 AN: 208906 AF XY: 0.000125

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.000343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000749 AC: 106 AN: 1415018 Hom.: 0 Cov.: 32 AF XY: 0.0000630 AC XY: 44 AN XY: 698808

African (AFR) AF: 0.00191 AC: 62 AN: 32476

American (AMR) AF: 0.000381 AC: 15 AN: 39336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22684

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1089988

Other (OTH) AF: 0.000257 AC: 15 AN: 58328

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74498

African (AFR) AF: 0.00207 AC: 86 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000733

ESP6500AA AF: 0.00209 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000275 AC: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.97
ClinPred		0.19	T
GERP RS		3.0
Varity_R		0.53
gMVP		0.77
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs28365116; hg19: chr16-1254375; COSMIC: COSV104419615; COSMIC: COSV104419615;