16-1219071-G-A

Variant names:

• chr16-1219071-G-A
• rs376628149
• NM_021098.3:c.5989G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021098.3(CACNA1H):​c.5989G>A​(p.Ala1997Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,549,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1997S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012807757).
• BP6: Variant 16-1219071-G-A is Benign according to our data. Variant chr16-1219071-G-A is described in ClinVar as Benign. ClinVar VariationId is 529696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00042 (64/152308) while in subpopulation EAS AF = 0.00617 (32/5188). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 64 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.5989G>A	p.Ala1997Thr	missense	Exon 34 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5971G>A	p.Ala1991Thr	missense	Exon 33 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.5989G>A	p.Ala1997Thr	missense	Exon 34 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6004G>A	p.Ala2002Thr	missense	Exon 33 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5974G>A	p.Ala1992Thr	missense	Exon 33 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000659 AC: 100 AN: 151836 AF XY: 0.000679

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00620

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000210 AC: 294 AN: 1397448 Hom.: 1 Cov.: 34 AF XY: 0.000242 AC XY: 167 AN XY: 689272

African (AFR) AF: 0.0000633 AC: 2 AN: 31598

American (AMR) AF: 0.000168 AC: 6 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00277 AC: 99 AN: 35736

South Asian (SAS) AF: 0.00120 AC: 95 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000287 AC: 31 AN: 1078762

Other (OTH) AF: 0.00105 AC: 61 AN: 57964

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152308 Hom.: 0 Cov.: 34 AF XY: 0.000524 AC XY: 39 AN XY: 74474

African (AFR) AF: 0.000265 AC: 11 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15310

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

East Asian (EAS) AF: 0.00617 AC: 32 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000329

ExAC AF: 0.000300 AC: 20

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.17
DANN	Benign	0.89
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.00090	D
MutationAssessor	Benign	0.77	N
PhyloP100		-1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.30
Sift	Benign	0.44	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.035
MVP		0.80
ClinPred		0.0059	T
GERP RS		-3.9
Varity_R		0.056
gMVP		0.21
Mutation Taster		=97/3	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: rs376628149; hg19: chr16-1269071;