rs58394372

chr16-1209290-G-A

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.3622G>A(p.Ala1208Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,577,374 control chromosomes in the GnomAD database, including 3 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1208A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.42

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=0.006581396).
• BP6: Variant 16-1209290-G-A is Benign according to our data. Variant chr16-1209290-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00177 (269/152252) while in subpopulation AFR AF= 0.00563 (234/41570). AF 95% confidence interval is 0.00504. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3622G>A	p.Ala1208Thr	missense_variant	17/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3622G>A	p.Ala1208Thr	missense_variant	17/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152138 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000479 AC: 92 AN: 191946 Hom.: 0 AF XY: 0.000411 AC XY: 44 AN XY: 106952

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000681

Gnomad SAS exome AF: 0.0000744

Gnomad FIN exome AF: 0.0000989

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 729 AN: 1425122 Hom.: 1 Cov.: 31 AF XY: 0.000493 AC XY: 349 AN XY: 707726

Gnomad4 AFR exome AF: 0.00572

Gnomad4 AMR exome AF: 0.000316

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000527

Gnomad4 SAS exome AF: 0.0000481

Gnomad4 FIN exome AF: 0.0000518

Gnomad4 NFE exome AF: 0.000445

Gnomad4 OTH exome AF: 0.000506

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152252 Hom.: 2 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74434

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.00194

ESP6500AA AF: 0.00312 AC: 11

ESP6500EA AF: 0.000533 AC: 4

ExAC AF: 0.000513 AC: 59

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.019
Dann	Benign	0.80
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.45	T;T;T;.
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	-0.47	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.70	T;.;T;T
Sift4G	Benign	0.39	T;.;T;T
Polyphen		0.0020	B;.;B;B
Vest4		0.047
MVP		0.48
ClinPred		0.0032	T
GERP RS		-8.4
Varity_R		0.029
gMVP		0.37

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: rs58394372; hg19: chr16-1259290; COSMIC: COSV100673545; COSMIC: COSV100673545;