chr16-1218494-C-T

Variant names:

• chr16-1218494-C-T
• rs2745136
• NM_021098.3:c.5730C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.5730C>T​(p.Asp1910Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,552,098 control chromosomes in the GnomAD database, including 291,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32402 hom., cov: 32)
  • Exomes 𝑓: 0.61 (259463 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.43
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-1218494-C-T is Benign according to our data. Variant chr16-1218494-C-T is described in ClinVar as Benign. ClinVar VariationId is 585653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5730C>T	p.Asp1910Asp	synonymous	Exon 33 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5712C>T	p.Asp1904Asp	synonymous	Exon 32 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5730C>T	p.Asp1910Asp	synonymous	Exon 33 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5745C>T	p.Asp1915Asp	synonymous	Exon 32 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5748C>T	p.Asp1916Asp	synonymous	Exon 32 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98414 AN: 151874 Hom.: 32373 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.653 AC: 102817 AN: 157464 AF XY: 0.641

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.737

Gnomad ASJ exome AF: 0.693

Gnomad EAS exome AF: 0.887

Gnomad FIN exome AF: 0.697

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.605 AC: 847097 AN: 1400106 Hom.: 259463 Cov.: 78 AF XY: 0.603 AC XY: 416553 AN XY: 690898

African (AFR) AF: 0.698 AC: 22131 AN: 31710

American (AMR) AF: 0.729 AC: 26223 AN: 35970

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 17504 AN: 25194

East Asian (EAS) AF: 0.901 AC: 32329 AN: 35896

South Asian (SAS) AF: 0.561 AC: 44563 AN: 79372

European-Finnish (FIN) AF: 0.690 AC: 33073 AN: 47946

Middle Eastern (MID) AF: 0.701 AC: 3991 AN: 5694

European-Non Finnish (NFE) AF: 0.584 AC: 630843 AN: 1080218

Other (OTH) AF: 0.627 AC: 36440 AN: 58106

GnomAD4 genome AF: 0.648 AC: 98490 AN: 151992 Hom.: 32402 Cov.: 32 AF XY: 0.655 AC XY: 48670 AN XY: 74288

African (AFR) AF: 0.690 AC: 28611 AN: 41444

American (AMR) AF: 0.701 AC: 10714 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2473 AN: 3472

East Asian (EAS) AF: 0.876 AC: 4485 AN: 5122

South Asian (SAS) AF: 0.564 AC: 2717 AN: 4818

European-Finnish (FIN) AF: 0.710 AC: 7521 AN: 10596

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39855 AN: 67942

Other (OTH) AF: 0.657 AC: 1388 AN: 2114

Alfa AF: 0.614 Hom.: 16244

Bravo AF: 0.657

Asia WGS AF: 0.723 AC: 2513 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 27, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.70
DANN	Benign	0.68
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2745136; hg19: chr16-1268494; COSMIC: COSV52353344; COSMIC: COSV52353344;