rs770718464

Variant names:

• chr16-1209413-G-A
• rs770718464
• ENST00000637236.3:n.3745G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000637236.3(CACNA1H):​n.3745G>A variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,596,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1H ENST00000637236.3 non_coding_transcript_exon
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.26
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000637236.3	n.3745G>A		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000348261.11	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.3705+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.3705+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000639478.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1657+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3191+1G>A		splice_donor_variant, intron_variant	Intron 16 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.3744+1G>A		splice_donor_variant, intron_variant	Intron 17 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000873 AC: 2 AN: 229008 AF XY: 0.00000789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444594 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719012

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.0000224 AC: 1 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111076

Other (OTH) AF: 0.0000166 AC: 1 AN: 60178

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000224 Hom.: 0

ExAC AF: 0.00000841 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Sep 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 17 of the CACNA1H gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs770718464, ExAC 0.009%) but has not been reported in the literature in individuals with a CACNA1H-related disease. ClinVar contains an entry for this variant (Variation ID: 265069). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547). However, current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA1H cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Jul 13, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3744+1G>A variant in the CACNA1H gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 17. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.3744+1G>A variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret c.3744+1G>A as a variant of uncertain significance, which may be related to the epilepsy reported

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.0	.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		8.3
PROVEAN	Benign	0.0	.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.0
GERP RS		3.5
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 3
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs770718464; hg19: chr16-1259413; COSMIC: COSV104661890; COSMIC: COSV104661890;