rs375589233

Positions:

• chr16-1220127-C-T

Variant summary

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

The ENST00000348261.11(CACNA1H):​c.6195C>T​(p.Ala2065=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,494,686 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: CACNA1H ENST00000348261.11 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.448

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=-0.76).
• BP6: Variant 16-1220127-C-T is Benign according to our data. Variant chr16-1220127-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1220127-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.448 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00168 (256/152328) while in subpopulation NFE AF= 0.0025 (170/68008). AF 95% confidence interval is 0.00219. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6195C>T	p.Ala2065=	synonymous_variant	35/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6195C>T	p.Ala2065=	synonymous_variant	35/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152210 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00200 AC: 291 AN: 145150 Hom.: 1 AF XY: 0.00209 AC XY: 167 AN XY: 79726

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00253 AC: 3392 AN: 1342358 Hom.: 7 Cov.: 31 AF XY: 0.00249 AC XY: 1637 AN XY: 657826

Gnomad4 AFR exome AF: 0.000257

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.00747

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000754

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152328 Hom.: 1 Cov.: 34 AF XY: 0.00160 AC XY: 119 AN XY: 74478

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.00190

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CACNA1H: BP4, BP7 -

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

Aug 12, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.1
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375589233; hg19: chr16-1270127;