16-1184871-A-G

Variant names:

• chr16-1184871-A-G
• rs7191344
• NM_021098.3:c.300-10101A>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.300-10101A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0826 in 151,552 control chromosomes in the GnomAD database, including 1,358 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 0.083 (1358 hom., cov: 34)
• Consequence: CACNA1H NM_021098.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.300-10101A>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.300-10101A>G		intron_variant	Intron 2 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.300-10101A>G		intron_variant	Intron 2 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.300-10101A>G		intron_variant	Intron 2 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.300-10101A>G		intron_variant	Intron 2 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.300-10101A>G		intron_variant	Intron 2 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.300-10101A>G		intron_variant	Intron 2 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.300-10101A>G		intron_variant	Intron 2 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.300-10101A>G		intron_variant	Intron 2 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.300-10101A>G		intron_variant	Intron 2 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.300-10101A>G		intron_variant	Intron 2 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.300-10101A>G		intron_variant	Intron 2 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.300-10101A>G		intron_variant	Intron 2 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.300-10101A>G		intron_variant	Intron 2 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.300-10101A>G		intron_variant	Intron 2 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.300-10101A>G		intron_variant	Intron 2 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.300-10101A>G		intron_variant	Intron 2 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.300-10101A>G		intron_variant	Intron 2 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.0824 AC: 12478 AN: 151434 Hom.: 1348 Cov.: 34

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.00846

Gnomad OTH AF: 0.0706

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

GnomAD4 genome AF: 0.0826 AC: 12521 AN: 151552 Hom.: 1358 Cov.: 34 AF XY: 0.0811 AC XY: 6012 AN XY: 74094

African (AFR) AF: 0.251 AC: 10331 AN: 41150

American (AMR) AF: 0.0512 AC: 781 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3468

East Asian (EAS) AF: 0.0369 AC: 188 AN: 5092

South Asian (SAS) AF: 0.0337 AC: 162 AN: 4810

European-Finnish (FIN) AF: 0.0209 AC: 220 AN: 10544

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.00847 AC: 575 AN: 67926

Other (OTH) AF: 0.0699 AC: 147 AN: 2104

Alfa AF: 0.0570 Hom.: 126

Bravo AF: 0.0921

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.59
PhyloP100		0.20
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: rs7191344; hg19: chr16-1234871;