rs57260464

Positions:

• chr16-1202274-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 ENST00000348261.11(CACNA1H):​c.1824G>A​(p.Leu608=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,579,758 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: CACNA1H ENST00000348261.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.515

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=-0.82).
• BP6: Variant 16-1202274-G-A is Benign according to our data. Variant chr16-1202274-G-A is described in ClinVar as [Benign]. Clinvar id is 460052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202274-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.515 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000971 (148/152342) while in subpopulation SAS AF= 0.00414 (20/4834). AF 95% confidence interval is 0.00274. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1824G>A	p.Leu608=	synonymous_variant	9/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1824G>A	p.Leu608=	synonymous_variant	9/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152224 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00175 AC: 332 AN: 189266 Hom.: 3 AF XY: 0.00203 AC XY: 211 AN XY: 103762

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00109 AC: 1554 AN: 1427416 Hom.: 19 Cov.: 56 AF XY: 0.00122 AC XY: 864 AN XY: 707054

Gnomad4 AFR exome AF: 0.000430

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000605

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.000971 AC: 148 AN: 152342 Hom.: 1 Cov.: 34 AF XY: 0.00102 AC XY: 76 AN XY: 74494

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00215 Hom.: 1

Bravo AF: 0.00112

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	clinical testing	Athena Diagnostics	Mar 08, 2018	- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.56

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: rs57260464; hg19: chr16-1252274;