chr16-1214974-G-A

Variant names:

• chr16-1214974-G-A
• rs58764017
• NM_021098.3:c.4932G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.4932G>A​(p.Ser1644Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,603,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (8 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15
• Publications: 1 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 16-1214974-G-A is Benign according to our data. Variant chr16-1214974-G-A is described in ClinVar as Benign. ClinVar VariationId is 529688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00526 (802/152332) while in subpopulation AFR AF = 0.0178 (741/41568). AF 95% confidence interval is 0.0168. There are 4 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 802 AD gene.

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.4932G>A	p.Ser1644Ser	splice_region synonymous	Exon 28 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.4914G>A	p.Ser1638Ser	splice_region synonymous	Exon 27 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.4932G>A	p.Ser1644Ser	splice_region synonymous	Exon 28 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.4947G>A	p.Ser1649Ser	splice_region synonymous	Exon 27 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.4950G>A	p.Ser1650Ser	splice_region synonymous	Exon 27 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00115 AC: 268 AN: 233822 AF XY: 0.000828

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000474

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000560 AC: 813 AN: 1451586 Hom.: 8 Cov.: 32 AF XY: 0.000466 AC XY: 336 AN XY: 721038

African (AFR) AF: 0.0189 AC: 629 AN: 33274

American (AMR) AF: 0.00104 AC: 45 AN: 43444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.000166 AC: 14 AN: 84456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52330

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.0000434 AC: 48 AN: 1107062

Other (OTH) AF: 0.00117 AC: 70 AN: 60038

GnomAD4 genome AF: 0.00526 AC: 802 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00497 AC XY: 370 AN XY: 74488

African (AFR) AF: 0.0178 AC: 741 AN: 41568

American (AMR) AF: 0.00248 AC: 38 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00158 Hom.: 2

Bravo AF: 0.00627

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Aug 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 24, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.051
DANN	Benign	0.89
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs58764017; hg19: chr16-1264974;