chr16-1193557-T-C

Variant names:

• chr16-1193557-T-C
• rs4347630
• NM_021098.3:c.300-1415T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021098.3(CACNA1H):​c.300-1415T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 152,336 control chromosomes in the GnomAD database, including 54,806 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (54806 hom., cov: 38)
• Consequence: CACNA1H NM_021098.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

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.300-1415T>C		intron	N/A	NP_066921.2
	CACNA1H	NM_001005407.2		c.300-1415T>C		intron	N/A	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.300-1415T>C		intron	N/A	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.300-1415T>C		intron	N/A	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.300-1415T>C		intron	N/A	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128884 AN: 152218 Hom.: 54753 Cov.: 38

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.827

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.847 AC: 129001 AN: 152336 Hom.: 54806 Cov.: 38 AF XY: 0.849 AC XY: 63213 AN XY: 74490

African (AFR) AF: 0.899 AC: 37397 AN: 41586

American (AMR) AF: 0.866 AC: 13251 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2646 AN: 3470

East Asian (EAS) AF: 0.979 AC: 5075 AN: 5186

South Asian (SAS) AF: 0.793 AC: 3827 AN: 4824

European-Finnish (FIN) AF: 0.862 AC: 9154 AN: 10622

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54942 AN: 68024

Other (OTH) AF: 0.827 AC: 1748 AN: 2114

Alfa AF: 0.825 Hom.: 17575

Bravo AF: 0.852

Asia WGS AF: 0.875 AC: 3043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.46
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs4347630; hg19: chr16-1243557;