rs755405205

Positions:

• chr16-1218283-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_021098.3(CACNA1H):​c.5519T>G​(p.Phe1840Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,400,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. F1840F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.79

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5519T>G	p.Phe1840Cys	missense_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5519T>G	p.Phe1840Cys	missense_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000559 AC: 9 AN: 160970 Hom.: 0 AF XY: 0.0000587 AC XY: 5 AN XY: 85160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000361

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1400612 Hom.: 0 Cov.: 32 AF XY: 0.00000724 AC XY: 5 AN XY: 691036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000251

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000372 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.5519T>G (p.F1840C) alteration is located in exon 33 (coding exon 32) of the CACNA1H gene. This alteration results from a T to G substitution at nucleotide position 5519, causing the phenylalanine (F) at amino acid position 1840 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1H protein function. ClinVar contains an entry for this variant (Variation ID: 572075). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is present in population databases (rs755405205, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1840 of the CACNA1H protein (p.Phe1840Cys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 30, 2023

PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D;D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.8	D;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.83
MutPred		0.76		Loss of helix (P = 0.028);.;.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs755405205; hg19: chr16-1268283;