rs57633676

Variant names:

• chr16-1208064-G-A
• rs57633676
• NM_021098.3:c.3206G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.3206G>A​(p.Arg1069Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,605,378 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16
• Publications: 3 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 (MetaRNN=0.0056758523).
• BP6: Variant 16-1208064-G-A is Benign according to our data. Variant chr16-1208064-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235710.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 = 0.00544 (828/152204) while in subpopulation AFR AF = 0.019 (789/41522). AF 95% confidence interval is 0.0179. There are 7 homozygotes in GnomAd4. There are 404 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 828 AD gene.

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.3206G>A	p.Arg1069Gln	missense	Exon 16 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.3206G>A	p.Arg1069Gln	missense	Exon 16 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.3206G>A	p.Arg1069Gln	missense	Exon 16 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.3206G>A	p.Arg1069Gln	missense	Exon 16 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.3206G>A	p.Arg1069Gln	missense	Exon 16 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152086 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00125 AC: 291 AN: 232472 AF XY: 0.00100

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000933

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000410

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.0000480

Gnomad OTH exome AF: 0.000524

GnomAD4 exome AF: 0.000547 AC: 795 AN: 1453174 Hom.: 4 Cov.: 33 AF XY: 0.000475 AC XY: 343 AN XY: 722066

African (AFR) AF: 0.0181 AC: 604 AN: 33302

American (AMR) AF: 0.00112 AC: 49 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.000229 AC: 9 AN: 39316

South Asian (SAS) AF: 0.0000946 AC: 8 AN: 84526

European-Finnish (FIN) AF: 0.000272 AC: 14 AN: 51526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.0000370 AC: 41 AN: 1108976

Other (OTH) AF: 0.00117 AC: 70 AN: 60016

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152204 Hom.: 7 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74404

African (AFR) AF: 0.0190 AC: 789 AN: 41522

American (AMR) AF: 0.00190 AC: 29 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00101 Hom.: 2

Bravo AF: 0.00606

ESP6500AA AF: 0.0173 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00175 AC: 211

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 14, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.0056
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0057	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.025	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.89
ClinPred		0.016	T
GERP RS		3.0
Varity_R		0.20
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs57633676; hg19: chr16-1258064;