rs58632975

chr16-1218419-G-Achr16-1218419-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_021098.3(CACNA1H):c.5655G>A(p.Ala1885=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,554,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A1885A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.83

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-1218419-G-A is Benign according to our data. Variant chr16-1218419-G-A is described in ClinVar as [Benign]. Clinvar id is 460149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000781 (119/152306) while in subpopulation NFE AF= 0.001 (68/68030). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5655G>A	p.Ala1885=	synonymous_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5655G>A	p.Ala1885=	synonymous_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152188 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000854 AC: 137 AN: 160384 Hom.: 0 AF XY: 0.000846 AC XY: 72 AN XY: 85108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000896

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00449

Gnomad NFE exome AF: 0.000830

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000725 AC: 1017 AN: 1401886 Hom.: 1 Cov.: 33 AF XY: 0.000688 AC XY: 476 AN XY: 691832

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000278

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00502

Gnomad4 NFE exome AF: 0.000663

Gnomad4 OTH exome AF: 0.000721

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152306 Hom.: 0 Cov.: 34 AF XY: 0.000779 AC XY: 58 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000453

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.39
Dann	Benign	0.82

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: rs58632975; hg19: chr16-1268419;