rs1555518356

Variant names:

• chr16-1213782-GC-TT
• rs1555518356
• NM_021098.3:c.4780_4781delGCinsTT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021098.3(CACNA1H):​c.4780_4781delGCinsTT​(p.Ala1594Phe) variant causes a missense, splice region change involving the alteration of a 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: 32)
• Consequence: CACNA1H NM_021098.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4780_4781delGCinsTT	p.Ala1594Phe	missense_variant, splice_region_variant		ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4780_4781delGCinsTT	p.Ala1594Phe	missense_variant, splice_region_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4762_4763delGCinsTT	p.Ala1588Phe	missense_variant, splice_region_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4741_4742delGCinsTT	p.Ala1581Phe	missense_variant, splice_region_variant		5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1018_1019delGCinsTT	p.Ala340Phe	missense_variant, splice_region_variant		1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1003_1004delGCinsTT	p.Ala335Phe	missense_variant, splice_region_variant		1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.985_986delGCinsTT	p.Ala329Phe	missense_variant, splice_region_variant		1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4718_4719delGCinsTT		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2631_*2632delGCinsTT		splice_region_variant, non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2631_*2632delGCinsTT		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1594 of the CACNA1H protein (p.Ala1594Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 460126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

not provided Uncertain:1

May 23, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CACNA1H gene. The c.4780_4781delGCinsTT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.4780_4781delGCinsTT variant is observed in 11/11210 (0.1%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). The c.4780_4781delGCinsTT variant results in an in-frame change of a single Alanine residue to a Phenylalanine residue, denoted p.Ala1594Phe. The c.4780_4781delGCinsTT variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555518356; hg19: chr16-1263782;