chr16-1207334-C-T

Variant names:

• chr16-1207334-C-T
• rs59090452
• NM_021098.3:c.2967C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.2967C>T​(p.Ser989Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,611,724 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0038 (12 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.501
• Publications: 3 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)

ENSG00000261294 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 16-1207334-C-T is Benign according to our data. Variant chr16-1207334-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.501 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (465/152264) while in subpopulation NFE AF = 0.00484 (329/68012). AF 95% confidence interval is 0.00441. There are 1 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2928C>T	p.Ser976Ser	synonymous_variant	Exon 14 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2928C>T	p.Ser976Ser	synonymous_variant	Exon 14 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2967C>T	p.Ser989Ser	synonymous_variant	Exon 14 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*880C>T		non_coding_transcript_exon_variant	Exon 14 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2414C>T		non_coding_transcript_exon_variant	Exon 13 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2967C>T		non_coding_transcript_exon_variant	Exon 14 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*880C>T		3_prime_UTR_variant	Exon 14 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2414C>T		3_prime_UTR_variant	Exon 13 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152146 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00349 AC: 854 AN: 244360 AF XY: 0.00342

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.000821

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00685

Gnomad NFE exome AF: 0.00562

Gnomad OTH exome AF: 0.00368

GnomAD4 exome AF: 0.00380 AC: 5542 AN: 1459460 Hom.: 12 Cov.: 33 AF XY: 0.00375 AC XY: 2725 AN XY: 725846

African (AFR) AF: 0.000568 AC: 19 AN: 33442

American (AMR) AF: 0.000921 AC: 41 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 83 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00733 AC: 386 AN: 52696

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00435 AC: 4833 AN: 1111156

Other (OTH) AF: 0.00297 AC: 179 AN: 60298

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152264 Hom.: 1 Cov.: 30 AF XY: 0.00298 AC XY: 222 AN XY: 74430

African (AFR) AF: 0.000578 AC: 24 AN: 41556

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00484 AC: 329 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00406 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1H-related disorder Benign:1

Aug 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.6
DANN	Benign	0.90
PhyloP100		-0.50
Mutation Taster		=99/1	polymorphism

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: rs59090452; hg19: chr16-1257334; COSMIC: COSV61990561; COSMIC: COSV61990561;