chr16-1175628-A-G

Variant names:

• chr16-1175628-A-G
• rs11640796
• NM_021098.3:c.300-19344A>G

Variant summary

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

The NM_021098.3(CACNA1H):​c.300-19344A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,082 control chromosomes in the GnomAD database, including 2,865 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 0.16 (2865 hom., cov: 33)
• Consequence: CACNA1H NM_021098.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.91
• Publications: 8 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.300-19344A>G		intron_variant	Intron 2 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.300-19344A>G		intron_variant	Intron 2 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.300-19344A>G		intron_variant	Intron 2 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.300-19344A>G		intron_variant	Intron 2 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.300-19344A>G		intron_variant	Intron 2 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.300-19344A>G		intron_variant	Intron 2 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.300-19344A>G		intron_variant	Intron 2 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.300-19344A>G		intron_variant	Intron 2 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.300-19344A>G		intron_variant	Intron 2 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.300-19344A>G		intron_variant	Intron 2 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.300-19344A>G		intron_variant	Intron 2 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.300-19344A>G		intron_variant	Intron 2 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.300-19344A>G		intron_variant	Intron 2 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.300-19344A>G		intron_variant	Intron 2 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.300-19344A>G		intron_variant	Intron 2 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.300-19344A>G		intron_variant	Intron 2 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.300-19344A>G		intron_variant	Intron 2 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.300-19344A>G		intron_variant	Intron 2 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24151 AN: 151962 Hom.: 2864 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.159 AC: 24153 AN: 152082 Hom.: 2865 Cov.: 33 AF XY: 0.169 AC XY: 12549 AN XY: 74346

African (AFR) AF: 0.105 AC: 4353 AN: 41504

American (AMR) AF: 0.114 AC: 1745 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3470

East Asian (EAS) AF: 0.668 AC: 3450 AN: 5164

South Asian (SAS) AF: 0.247 AC: 1189 AN: 4822

European-Finnish (FIN) AF: 0.277 AC: 2925 AN: 10566

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9867 AN: 67968

Other (OTH) AF: 0.143 AC: 302 AN: 2106

Alfa AF: 0.150 Hom.: 6883

Bravo AF: 0.146

Asia WGS AF: 0.391 AC: 1359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.075
DANN	Benign	0.15
PhyloP100		-2.9
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: rs11640796; hg19: chr16-1225628; COSMIC: COSV62002077;