rs58594334

Variant names:

• chr16-1209282-G-A
• rs58594334
• NM_021098.3:c.3614G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1209282-G-A
• chr16-1209282-G-C
• chr16-1209282-G-T

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.3614G>A​(p.Arg1205Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,564,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1205P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.26
• Publications: 2 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=0.0078059435).
• BP6: Variant 16-1209282-G-A is Benign according to our data. Variant chr16-1209282-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460089.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 = 0.000716 (109/152260) while in subpopulation AFR AF = 0.00257 (107/41580). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.3575G>A	p.Arg1192Gln	missense_variant	Exon 17 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.3575G>A	p.Arg1192Gln	missense_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.3614G>A	p.Arg1205Gln	missense_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1527G>A		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3061G>A		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.3614G>A		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*1527G>A		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3061G>A		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 40 AN: 170532 AF XY: 0.000190

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.000253

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 184 AN: 1411842 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 75 AN XY: 699806

African (AFR) AF: 0.00296 AC: 96 AN: 32408

American (AMR) AF: 0.000233 AC: 9 AN: 38700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.0000541 AC: 2 AN: 36998

South Asian (SAS) AF: 0.0000244 AC: 2 AN: 81870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000558 AC: 61 AN: 1093154

Other (OTH) AF: 0.000238 AC: 14 AN: 58794

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74448

African (AFR) AF: 0.00257 AC: 107 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000929

ESP6500AA AF: 0.000623 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000176 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Sep 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1H-related disorder Benign:1

Jan 05, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 27, 2025

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
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.082	T;.;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.63	T;T;T;.
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Benign	1.9	L;.;L;L
PhyloP100		1.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.48	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.61	T;.;T;T
Sift4G	Benign	0.73	T;.;T;T
Polyphen		0.015	B;.;B;B
Vest4		0.19
MVP		0.68
ClinPred		0.0027	T
GERP RS		1.3
Varity_R		0.052
gMVP		0.42
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs58594334; hg19: chr16-1259282;