NM_021098.3:c.1107T>C

Variant names:

• chr16-1200559-T-C
• rs8044363
• NM_021098.3:c.1107T>C

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.1107T>C​(p.Ile369Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,611,322 control chromosomes in the GnomAD database, including 150,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14162 hom., cov: 33)
  • Exomes 𝑓: 0.42 (136779 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.69
• Publications: 17 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)

LOC124903623 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-1200559-T-C is Benign according to our data. Variant chr16-1200559-T-C is described in ClinVar as Benign. ClinVar VariationId is 166755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 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.1107T>C	p.Ile369Ile	synonymous	Exon 7 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.1107T>C	p.Ile369Ile	synonymous	Exon 7 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.1107T>C	p.Ile369Ile	synonymous	Exon 7 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.1107T>C	p.Ile369Ile	synonymous	Exon 7 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.1107T>C	p.Ile369Ile	synonymous	Exon 7 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64020 AN: 151904 Hom.: 14133 Cov.: 33

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.370 AC: 90696 AN: 245158 AF XY: 0.371

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.424 AC: 619188 AN: 1459300 Hom.: 136779 Cov.: 46 AF XY: 0.420 AC XY: 304849 AN XY: 725992

African (AFR) AF: 0.487 AC: 16299 AN: 33462

American (AMR) AF: 0.270 AC: 12087 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6554 AN: 26100

East Asian (EAS) AF: 0.0844 AC: 3350 AN: 39690

South Asian (SAS) AF: 0.313 AC: 26969 AN: 86238

European-Finnish (FIN) AF: 0.491 AC: 25321 AN: 51594

Middle Eastern (MID) AF: 0.271 AC: 1563 AN: 5764

European-Non Finnish (NFE) AF: 0.453 AC: 503390 AN: 1111448

Other (OTH) AF: 0.392 AC: 23655 AN: 60318

GnomAD4 genome AF: 0.422 AC: 64089 AN: 152022 Hom.: 14162 Cov.: 33 AF XY: 0.417 AC XY: 31000 AN XY: 74294

African (AFR) AF: 0.492 AC: 20410 AN: 41446

American (AMR) AF: 0.308 AC: 4703 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 855 AN: 3468

East Asian (EAS) AF: 0.115 AC: 595 AN: 5166

South Asian (SAS) AF: 0.299 AC: 1444 AN: 4826

European-Finnish (FIN) AF: 0.497 AC: 5260 AN: 10580

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29658 AN: 67940

Other (OTH) AF: 0.380 AC: 800 AN: 2108

Alfa AF: 0.398 Hom.: 7728

Bravo AF: 0.411

Asia WGS AF: 0.229 AC: 796 AN: 3478

EpiCase AF: 0.404

EpiControl AF: 0.408

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12891677, 17156077)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Apr 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	1.8
DANN	Benign	0.79
PhyloP100		-2.7
Mutation Taster		=95/5	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: rs8044363; hg19: chr16-1250559; COSMIC: COSV61982985; COSMIC: COSV61982985;