16-1195427-C-G

Variant names:

• chr16-1195427-C-G
• rs577701046
• NM_021098.3:c.412-5C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021098.3(CACNA1H):​c.412-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001985
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.41
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.412-44C>G		intron_variant	Intron 3 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.412-44C>G		intron_variant	Intron 3 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.412-5C>G		splice_region_variant, intron_variant	Intron 3 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 10, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.72
DANN	Benign	0.47
PhyloP100		-2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.15		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: rs577701046; hg19: chr16-1245427;