rs58812334

Positions:

• chr16-1209406-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.3738G>A​(p.Ser1246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,597,486 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 33)
  • Exomes 𝑓: 0.016 (204 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.93

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 16-1209406-G-A is Benign according to our data. Variant chr16-1209406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1209406-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1792/152324) while in subpopulation NFE AF= 0.0186 (1263/68024). AF 95% confidence interval is 0.0177. There are 11 homozygotes in gnomad4. There are 822 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3738G>A	p.Ser1246=	synonymous_variant	17/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3738G>A	p.Ser1246=	synonymous_variant	17/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1792 AN: 152206 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.0683

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0115 AC: 2638 AN: 230162 Hom.: 26 AF XY: 0.0115 AC XY: 1465 AN XY: 127336

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00452

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0158 AC: 22779 AN: 1445162 Hom.: 204 Cov.: 32 AF XY: 0.0154 AC XY: 11056 AN XY: 719284

Gnomad4 AFR exome AF: 0.00300

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00399

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.00718

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.0118 AC: 1792 AN: 152324 Hom.: 11 Cov.: 33 AF XY: 0.0110 AC XY: 822 AN XY: 74474

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0134 Hom.: 4

Bravo AF: 0.0126

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0180

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 18, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.8
DANN	Benign	0.76

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: rs58812334; hg19: chr16-1259406;