rs59650398

Variant names:

• chr16-1200446-G-A
• rs59650398
• NM_021098.3:c.994G>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.994G>A​(p.Ala332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,611,106 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 33)
  • Exomes 𝑓: 0.017 (282 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.957
• 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 (MetaRNN=0.0031196177).
• BP6: Variant 16-1200446-G-A is Benign according to our data. Variant chr16-1200446-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.014 (2135/152254) while in subpopulation SAS AF = 0.0274 (132/4826). AF 95% confidence interval is 0.0236. There are 23 homozygotes in GnomAd4. There are 1066 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.955G>A	p.Ala319Thr	missense_variant	Exon 7 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.955G>A	p.Ala319Thr	missense_variant	Exon 7 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.994G>A	p.Ala332Thr	missense_variant	Exon 7 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*441G>A		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.994G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*441G>A		3_prime_UTR_variant	Exon 6 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2137 AN: 152136 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0168 AC: 4110 AN: 244950 AF XY: 0.0183

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0471

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0171 AC: 24877 AN: 1458852 Hom.: 282 Cov.: 35 AF XY: 0.0177 AC XY: 12862 AN XY: 725818

African (AFR) AF: 0.00275 AC: 92 AN: 33464

American (AMR) AF: 0.0114 AC: 510 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 1204 AN: 26094

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.0278 AC: 2397 AN: 86228

European-Finnish (FIN) AF: 0.0147 AC: 749 AN: 51084

Middle Eastern (MID) AF: 0.0387 AC: 223 AN: 5768

European-Non Finnish (NFE) AF: 0.0167 AC: 18530 AN: 1111550

Other (OTH) AF: 0.0194 AC: 1168 AN: 60316

GnomAD4 genome AF: 0.0140 AC: 2135 AN: 152254 Hom.: 23 Cov.: 33 AF XY: 0.0143 AC XY: 1066 AN XY: 74440

African (AFR) AF: 0.00318 AC: 132 AN: 41558

American (AMR) AF: 0.0173 AC: 264 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5150

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4826

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10622

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0177 AC: 1206 AN: 68004

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0172 Hom.: 57

Bravo AF: 0.0133

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00190 AC: 8

ESP6500EA AF: 0.0173 AC: 145

ExAC AF: 0.0166 AC: 2000

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

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

- -

Jul 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 6 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 09/25/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.20
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.75	T;T;T;.
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.40	N;.;N;N
PhyloP100		-0.96
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.36	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.44	T;.;T;T
Sift4G	Benign	0.75	T;.;T;T
Polyphen		0.0080	B;.;B;B
Vest4		0.15
ClinPred		0.00054	T
GERP RS		3.2
Varity_R		0.049
gMVP		0.75
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs59650398; hg19: chr16-1250446; COSMIC: COSV61989295; COSMIC: COSV61989295;