rs59090452

chr16-1207334-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):c.2967C>T(p.Ser989=) 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:4
• Conservation: PhyloP100: -0.501

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 460074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1207334-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.2967C>T	p.Ser989=	synonymous_variant	14/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2967C>T	p.Ser989=	synonymous_variant	14/35	1	NM_021098.3	P4

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

GnomAD3 exomes AF: 0.00349 AC: 854 AN: 244360 Hom.: 4 AF XY: 0.00342 AC XY: 455 AN XY: 133070

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 SAS exome AF: 0.0000333

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

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000921

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00733

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00297

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

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00189

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CACNA1H: BP4, BP7, BS2 -

CACNA1H-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2019

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.6
Dann	Benign	0.90

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

Publications

LitVar

Other links and lift over

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