rs60218977

chr16-1218257-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):c.5493C>T(p.Tyr1831=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,551,042 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0064 (53 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.58

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-1218257-C-T is Benign according to our data. Variant chr16-1218257-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218257-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00522 (795/152368) while in subpopulation NFE AF= 0.00573 (390/68036). AF 95% confidence interval is 0.00526. There are 7 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 795 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5493C>T	p.Tyr1831=	synonymous_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5493C>T	p.Tyr1831=	synonymous_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152250 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00567 AC: 892 AN: 157218 Hom.: 9 AF XY: 0.00545 AC XY: 454 AN XY: 83238

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00636 AC: 8899 AN: 1398674 Hom.: 53 Cov.: 32 AF XY: 0.00624 AC XY: 4307 AN XY: 689932

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.00651

Gnomad4 OTH exome AF: 0.00561

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152368 Hom.: 7 Cov.: 34 AF XY: 0.00581 AC XY: 433 AN XY: 74516

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0288

Gnomad4 NFE AF: 0.00573

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00527 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1H: BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

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

Jul 26, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	5.4
Dann	Benign	0.93

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: rs60218977; hg19: chr16-1268257;