NM_021098.3:c.5418G>C

Variant names:

• chr16-1218013-G-C
• rs57135930
• NM_021098.3:c.5418G>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.5418G>C​(p.Thr1806Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,600,998 control chromosomes in the GnomAD database, including 3,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1806T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (248 hom., cov: 34)
  • Exomes 𝑓: 0.061 (3054 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.87
• Publications: 5 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=-0.84).
• BP6: Variant 16-1218013-G-C is Benign according to our data. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218013-G-C is described in CliVar as Benign. Clinvar id is 585650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.5433G>C	p.Thr1811Thr	synonymous_variant	Exon 31 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.5436G>C	p.Thr1812Thr	synonymous_variant	Exon 31 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.5400G>C	p.Thr1800Thr	synonymous_variant	Exon 31 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.5433G>C	p.Thr1811Thr	synonymous_variant	Exon 32 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.5379G>C	p.Thr1793Thr	synonymous_variant	Exon 32 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.5400G>C	p.Thr1800Thr	synonymous_variant	Exon 31 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.5361G>C	p.Thr1787Thr	synonymous_variant	Exon 31 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.5400G>C	p.Thr1800Thr	synonymous_variant	Exon 31 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.5418G>C	p.Thr1806Thr	synonymous_variant	Exon 32 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.5418G>C		non_coding_transcript_exon_variant	Exon 32 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*1370G>C		non_coding_transcript_exon_variant	Exon 31 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*499G>C		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3269G>C		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4862G>C		non_coding_transcript_exon_variant	Exon 30 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*392G>C		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*277G>C		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1030G>C		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*85G>C		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*85G>C		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.5400G>C		non_coding_transcript_exon_variant	Exon 31 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.5418G>C		non_coding_transcript_exon_variant	Exon 32 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.5418G>C		non_coding_transcript_exon_variant	Exon 32 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*534G>C		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*1370G>C		3_prime_UTR_variant	Exon 31 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*499G>C		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3269G>C		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4862G>C		3_prime_UTR_variant	Exon 30 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*392G>C		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*277G>C		3_prime_UTR_variant	Exon 32 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1030G>C		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*85G>C		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*85G>C		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1	n.*534G>C		3_prime_UTR_variant	Exon 32 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7150 AN: 152194 Hom.: 247 Cov.: 34

Gnomad AFR AF: 0.00941

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0786

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0587

GnomAD2 exomes AF: 0.0546 AC: 12461 AN: 228046 AF XY: 0.0587

Gnomad AFR exome AF: 0.00869

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0676

GnomAD4 exome AF: 0.0606 AC: 87838 AN: 1448686 Hom.: 3054 Cov.: 32 AF XY: 0.0618 AC XY: 44455 AN XY: 719566

African (AFR) AF: 0.00848 AC: 282 AN: 33244

American (AMR) AF: 0.0321 AC: 1394 AN: 43368

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 2419 AN: 25848

East Asian (EAS) AF: 0.000205 AC: 8 AN: 39080

South Asian (SAS) AF: 0.0845 AC: 7122 AN: 84258

European-Finnish (FIN) AF: 0.0512 AC: 2617 AN: 51140

Middle Eastern (MID) AF: 0.0844 AC: 485 AN: 5748

European-Non Finnish (NFE) AF: 0.0632 AC: 69867 AN: 1106164

Other (OTH) AF: 0.0609 AC: 3644 AN: 59836

GnomAD4 genome AF: 0.0470 AC: 7152 AN: 152312 Hom.: 248 Cov.: 34 AF XY: 0.0455 AC XY: 3390 AN XY: 74476

African (AFR) AF: 0.00938 AC: 390 AN: 41580

American (AMR) AF: 0.0438 AC: 670 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 316 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0793 AC: 382 AN: 4820

European-Finnish (FIN) AF: 0.0489 AC: 519 AN: 10620

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4569 AN: 68014

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0547 Hom.: 96

Bravo AF: 0.0421

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 22, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.75
PhyloP100		-7.9
Mutation Taster		=78/22	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: rs57135930; hg19: chr16-1268013; COSMIC: COSV52359194; COSMIC: COSV52359194;