rs59709076

Variant names:

• chr16-1200279-G-A
• rs59709076
• NM_021098.3:c.827G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1200279-G-A
• chr16-1200279-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.827G>A​(p.Arg276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,601,618 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.75
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 16-1200279-G-A is Benign according to our data. Variant chr16-1200279-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460192.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00317 (482/152274) while in subpopulation AFR AF = 0.0112 (464/41546). AF 95% confidence interval is 0.0103. There are 3 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 482 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.827G>A	p.Arg276Gln	missense	Exon 7 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.827G>A	p.Arg276Gln	missense	Exon 7 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.827G>A	p.Arg276Gln	missense	Exon 7 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.827G>A	p.Arg276Gln	missense	Exon 7 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.827G>A	p.Arg276Gln	missense	Exon 7 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152156 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

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: 0.000957

GnomAD2 exomes AF: 0.000679 AC: 159 AN: 234252 AF XY: 0.000594

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000286 AC: 415 AN: 1449344 Hom.: 3 Cov.: 32 AF XY: 0.000243 AC XY: 175 AN XY: 719362

African (AFR) AF: 0.0106 AC: 352 AN: 33142

American (AMR) AF: 0.000575 AC: 25 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39338

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105884

Other (OTH) AF: 0.000551 AC: 33 AN: 59860

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152274 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74434

African (AFR) AF: 0.0112 AC: 464 AN: 41546

American (AMR) AF: 0.000980 AC: 15 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000735 Hom.: 0

Bravo AF: 0.00351

ESP6500AA AF: 0.0103 AC: 43

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000938 AC: 113

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.827G>A (p.R276Q) alteration is located in exon 7 (coding exon 6) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 827, causing the arginine (R) at amino acid position 276 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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	0.073
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.0025
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.083	T
Sift4G	Benign	0.55	T
Polyphen		0.96	D
Vest4		0.28
MVP		0.80
ClinPred		0.0082	T
GERP RS		3.4
Varity_R		0.054
gMVP		0.80
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59709076; hg19: chr16-1250279;