chr16-1202259-A-G

Variant names:

• chr16-1202259-A-G
• rs9934839
• NM_021098.3:c.1809A>G

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.1809A>G​(p.Arg603Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,571,310 control chromosomes in the GnomAD database, including 194,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19495 hom., cov: 35)
  • Exomes 𝑓: 0.49 (174978 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.570
• Publications: 13 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=-0.73).
• BP6: Variant 16-1202259-A-G is Benign according to our data. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in CliVar as Benign. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.1770A>G	p.Arg590Arg	synonymous_variant	Exon 9 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.1770A>G	p.Arg590Arg	synonymous_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.1809A>G	p.Arg603Arg	synonymous_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000711442.1	n.*1256A>G		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.1809A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*1256A>G		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1	n.1385+424A>G		intron_variant	Intron 9 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75082 AN: 152050 Hom.: 19461 Cov.: 35

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.418 AC: 74333 AN: 177792 AF XY: 0.419

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.488 AC: 692436 AN: 1419142 Hom.: 174978 Cov.: 64 AF XY: 0.483 AC XY: 339037 AN XY: 702244

African (AFR) AF: 0.588 AC: 18978 AN: 32260

American (AMR) AF: 0.315 AC: 12256 AN: 38862

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8404 AN: 25426

East Asian (EAS) AF: 0.0946 AC: 3494 AN: 36930

South Asian (SAS) AF: 0.351 AC: 28319 AN: 80584

European-Finnish (FIN) AF: 0.524 AC: 25194 AN: 48036

Middle Eastern (MID) AF: 0.370 AC: 2109 AN: 5704

European-Non Finnish (NFE) AF: 0.519 AC: 566732 AN: 1092518

Other (OTH) AF: 0.458 AC: 26950 AN: 58822

GnomAD4 genome AF: 0.494 AC: 75158 AN: 152168 Hom.: 19495 Cov.: 35 AF XY: 0.488 AC XY: 36338 AN XY: 74410

African (AFR) AF: 0.593 AC: 24604 AN: 41508

American (AMR) AF: 0.372 AC: 5692 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1129 AN: 3468

East Asian (EAS) AF: 0.127 AC: 656 AN: 5168

South Asian (SAS) AF: 0.340 AC: 1645 AN: 4834

European-Finnish (FIN) AF: 0.531 AC: 5630 AN: 10608

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.505 AC: 34291 AN: 67964

Other (OTH) AF: 0.462 AC: 977 AN: 2114

Alfa AF: 0.489 Hom.: 6571

Bravo AF: 0.487

Asia WGS AF: 0.254 AC: 887 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.1
DANN	Benign	0.42
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9934839; hg19: chr16-1252259; COSMIC: COSV61990652; COSMIC: COSV61990652;