chr16-1208033-G-T

Variant names:

• chr16-1208033-G-T
• rs41292285
• NM_021098.3:c.3175G>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.3175G>T​(p.Ala1059Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,606,222 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1059A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (94 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.90
• 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=0.007585913).
• BP6: Variant 16-1208033-G-T is Benign according to our data. Variant chr16-1208033-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00705 (1073/152182) while in subpopulation AMR AF = 0.0112 (172/15292). AF 95% confidence interval is 0.00987. There are 7 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1073 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.3175G>T	p.Ala1059Ser	missense	Exon 16 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.3175G>T	p.Ala1059Ser	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.3175G>T	p.Ala1059Ser	missense	Exon 16 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.3175G>T	p.Ala1059Ser	missense	Exon 16 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.3175G>T	p.Ala1059Ser	missense	Exon 16 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1075 AN: 152064 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00725 AC: 1707 AN: 235422 AF XY: 0.00757

Gnomad AFR exome AF: 0.00206

Gnomad AMR exome AF: 0.00636

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00957 AC: 13920 AN: 1454040 Hom.: 94 Cov.: 33 AF XY: 0.00945 AC XY: 6827 AN XY: 722570

African (AFR) AF: 0.00294 AC: 98 AN: 33340

American (AMR) AF: 0.00660 AC: 290 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 25982

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39346

South Asian (SAS) AF: 0.00394 AC: 334 AN: 84676

European-Finnish (FIN) AF: 0.000928 AC: 48 AN: 51744

Middle Eastern (MID) AF: 0.0398 AC: 225 AN: 5652

European-Non Finnish (NFE) AF: 0.0107 AC: 11861 AN: 1109220

Other (OTH) AF: 0.0109 AC: 654 AN: 60114

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152182 Hom.: 7 Cov.: 32 AF XY: 0.00665 AC XY: 495 AN XY: 74424

African (AFR) AF: 0.00207 AC: 86 AN: 41500

American (AMR) AF: 0.0112 AC: 172 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 682 AN: 67998

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00923 Hom.: 6

Bravo AF: 0.00753

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00247 AC: 10

ESP6500EA AF: 0.0100 AC: 83

ExAC AF: 0.00649 AC: 783

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Jun 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17696120, 25525159, 26706850)

Jun 06, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0076	T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.56	T
Sift4G	Benign	0.66	T
Polyphen		0.91	P
Vest4		0.47
MVP		0.88
ClinPred		0.022	T
GERP RS		3.0
Varity_R		0.081
gMVP		0.38
Mutation Taster		=100/0	polymorphism

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: rs41292285; hg19: chr16-1258033; COSMIC: COSV61998622; COSMIC: COSV61998622;