chr16-1195062-C-T

Position:

• chr16-1195062-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.390C>T​(p.Ser130Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,605,332 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (292 hom., cov: 29)
  • Exomes 𝑓: 0.0038 (298 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.01

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]

CACNA1H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-1195062-C-T is Benign according to our data. Variant chr16-1195062-C-T is described in ClinVar as [Benign]. Clinvar id is 460099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195062-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.390C>T	p.Ser130Ser	synonymous_variant	3/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.390C>T	p.Ser130Ser	synonymous_variant	3/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.390C>T	p.Ser130Ser	synonymous_variant	2/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.390C>T	p.Ser130Ser	synonymous_variant	3/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.390C>T		non_coding_transcript_exon_variant	3/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.390C>T		non_coding_transcript_exon_variant	3/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5230 AN: 150376 Hom.: 289 Cov.: 29

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000649

Gnomad OTH AF: 0.0247

GnomAD3 exomes AF: 0.00919 AC: 2277 AN: 247862 Hom.: 119 AF XY: 0.00688 AC XY: 928 AN XY: 134836

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00716

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00384 AC: 5585 AN: 1454842 Hom.: 298 Cov.: 32 AF XY: 0.00335 AC XY: 2423 AN XY: 722958

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00783

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.00900

GnomAD4 genome AF: 0.0349 AC: 5255 AN: 150490 Hom.: 292 Cov.: 29 AF XY: 0.0332 AC XY: 2441 AN XY: 73450

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000649

Gnomad4 OTH AF: 0.0244

Alfa AF: 0.0196 Hom.: 106

Bravo AF: 0.0398

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.72
CADD	Benign	1.4
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59794024; hg19: chr16-1245062;