rs768475346

Positions:

• chr16-1202227-CATGCCGCAGCCA-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

The NM_021098.3(CACNA1H):​c.1778_1789delATGCCGCAGCCA​(p.His593_Thr597delinsPro) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,555,876 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CACNA1H NM_021098.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.17

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021098.3.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000315 (48/152374) while in subpopulation AMR AF= 0.00209 (32/15310). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1778_1789delATGCCGCAGCCA	p.His593_Thr597delinsPro	disruptive_inframe_deletion	9/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1778_1789delATGCCGCAGCCA	p.His593_Thr597delinsPro	disruptive_inframe_deletion	9/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1778_1789delATGCCGCAGCCA	p.His593_Thr597delinsPro	disruptive_inframe_deletion	8/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1739_1750delATGCCGCAGCCA	p.His580_Thr584delinsPro	disruptive_inframe_deletion	9/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1778_1789delATGCCGCAGCCA		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1385+393_1385+404delATGCCGCAGCCA		intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152256 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000111 AC: 17 AN: 153320 Hom.: 0 AF XY: 0.000132 AC XY: 11 AN XY: 83298

Gnomad AFR exome AF: 0.000142

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.000136 AC: 191 AN: 1403502 Hom.: 1 AF XY: 0.000140 AC XY: 97 AN XY: 693110

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.000551

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152374 Hom.: 1 Cov.: 34 AF XY: 0.000403 AC XY: 30 AN XY: 74518

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000570

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperaldosteronism, familial, type IV Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 17, 2020

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This variant, c.1778_1789del, is a complex sequence change that results in the deletion of 5 and insertion of 1 amino acid(s) in the CACNA1H protein (p.His593_Thr597delinsPro). This variant is present in population databases (rs768475346, gnomAD 0.03%). 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: 573615). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 15, 2017

- -

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: rs768475346; hg19: chr16-1252227;