rs35509671

chr16-1195916-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.546-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,610,874 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (94 hom.)
• Consequence: CACNA1H NM_021098.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001854
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.434

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-1195916-C-T is Benign according to our data. Variant chr16-1195916-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195916-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0127 (1934/152342) while in subpopulation EAS AF= 0.047 (243/5166). AF 95% confidence interval is 0.0422. There are 24 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1936 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.546-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.546-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152224 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0471

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00903

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0124 AC: 3075 AN: 247466 Hom.: 60 AF XY: 0.0108 AC XY: 1460 AN XY: 134718

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.0488

Gnomad SAS exome AF: 0.00915

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.000744

Gnomad OTH exome AF: 0.00830

GnomAD4 exome AF: 0.00407 AC: 5939 AN: 1458532 Hom.: 94 Cov.: 32 AF XY: 0.00395 AC XY: 2870 AN XY: 725692

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0366

Gnomad4 SAS exome AF: 0.00796

Gnomad4 FIN exome AF: 0.00880

Gnomad4 NFE exome AF: 0.000442

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.0127 AC: 1934 AN: 152342 Hom.: 24 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74478

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0470

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.00903

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00784 Hom.: 5

Bravo AF: 0.0150

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

CACNA1H-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 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

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.5
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs35509671; hg19: chr16-1245916;