rs59650398

chr16-1200446-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.994G>A(p.Ala332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,611,106 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 33)
  • Exomes 𝑓: 0.017 (282 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.957

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=0.0031196177).
• BP6: Variant 16-1200446-G-A is Benign according to our data. Variant chr16-1200446-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1200446-G-A is described in Lovd as [Benign]. Variant chr16-1200446-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.014 (2135/152254) while in subpopulation SAS AF= 0.0274 (132/4826). AF 95% confidence interval is 0.0236. There are 23 homozygotes in gnomad4. There are 1066 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.994G>A	p.Ala332Thr	missense_variant	7/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.994G>A	p.Ala332Thr	missense_variant	7/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2137 AN: 152136 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0168 AC: 4110 AN: 244950 Hom.: 63 AF XY: 0.0183 AC XY: 2449 AN XY: 133778

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0471

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0268

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0171 AC: 24877 AN: 1458852 Hom.: 282 Cov.: 35 AF XY: 0.0177 AC XY: 12862 AN XY: 725818

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0461

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0278

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0140 AC: 2135 AN: 152254 Hom.: 23 Cov.: 33 AF XY: 0.0143 AC XY: 1066 AN XY: 74440

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0191 Hom.: 16

Bravo AF: 0.0133

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00190 AC: 8

ESP6500EA AF: 0.0173 AC: 145

ExAC AF: 0.0166 AC: 2000

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2020

- -

Epilepsy, childhood absence, susceptibility to, 6 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 09/25/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.20
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.75	T;T;T;.
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.40	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.36	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.44	T;.;T;T
Sift4G	Benign	0.75	T;.;T;T
Polyphen		0.0080	B;.;B;B
Vest4		0.15
ClinPred		0.00054	T
GERP RS		3.2
Varity_R		0.049
gMVP		0.75

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: rs59650398; hg19: chr16-1250446; COSMIC: COSV61989295; COSMIC: COSV61989295;