16-1202114-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.1664C>T(p.Ala555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,546,262 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A555T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (9 hom., cov: 34)
  • Exomes 𝑓: 0.015 (180 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.12

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021456778).
• BP6: Variant 16-1202114-C-T is Benign according to our data. Variant chr16-1202114-C-T is described in ClinVar as [Benign]. Clinvar id is 96001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202114-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2208/152338) while in subpopulation NFE AF= 0.0166 (1132/68016). AF 95% confidence interval is 0.0158. There are 9 homozygotes in gnomad4. There are 1033 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 2206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1664C>T	p.Ala555Val	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1664C>T	p.Ala555Val	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2206 AN: 152220 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0111 AC: 1547 AN: 139104 Hom.: 11 AF XY: 0.0108 AC XY: 817 AN XY: 75476

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00849

Gnomad ASJ exome AF: 0.00959

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000536

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.0154 AC: 21496 AN: 1393924 Hom.: 180 Cov.: 36 AF XY: 0.0149 AC XY: 10270 AN XY: 687418

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.00842

Gnomad4 ASJ exome AF: 0.00928

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000543

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0145 AC: 2208 AN: 152338 Hom.: 9 Cov.: 34 AF XY: 0.0139 AC XY: 1033 AN XY: 74486

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0152 Hom.: 7

Bravo AF: 0.0148

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00958 AC: 24

ESP6500EA AF: 0.0162 AC: 96

ExAC AF: 0.00573 AC: 429

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2013

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.21
Dann	Benign	0.90
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.19	T;T;T;.
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.42	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.18	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.48	T;.;T;T
Sift4G	Benign	0.55	T;.;T;T
Polyphen		0.0020	B;.;B;B
Vest4		0.077
ClinPred		0.00092	T
GERP RS		-2.5
Varity_R		0.042
gMVP		0.29

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: rs9924241; hg19: chr16-1252114;