rs1555514742

Variant names:

• chr16-1207847-ACTC-A
• rs1555514742
• NM_021098.3:c.3143_3145delTCC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_021098.3(CACNA1H):​c.3143_3145delTCC​(p.Leu1048del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1H NM_021098.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021098.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.3104_3106delTCC	p.Leu1035del	disruptive_inframe_deletion	Exon 15 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.3104_3106delTCC	p.Leu1035del	disruptive_inframe_deletion	Exon 15 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.3143_3145delTCC	p.Leu1048del	disruptive_inframe_deletion	Exon 15 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1056_*1058delTCC		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2590_*2592delTCC		non_coding_transcript_exon_variant	Exon 14 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.3143_3145delTCC		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*1056_*1058delTCC		3_prime_UTR_variant	Exon 15 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2590_*2592delTCC		3_prime_UTR_variant	Exon 14 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has not been reported in the literature in individuals with CACNA1H-related disease. This variant is not present in population databases (ExAC no frequency). This variant, c.3143_3145delTCC, results in the deletion of 1 amino acid of the CACNA1H protein (p.Leu1048del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4

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: rs1555514742; hg19: chr16-1257847;