rs377030217

chr16-1210360-G-Achr16-1210360-G-Cchr16-1210360-G-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.3846-10G>A 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 0.00188 in 159,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002291
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.79

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=-0.89).
• BP6: Variant 16-1210360-G-A is Benign according to our data. Variant chr16-1210360-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 585637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (34/14286) while in subpopulation NFE AF= 0.00474 (27/5696). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3846-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3846-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 34 AN: 14224 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00421

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00474

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000724 AC: 29 AN: 40034 Hom.: 0 AF XY: 0.000905 AC XY: 19 AN XY: 21006

Gnomad AFR exome AF: 0.000359

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000430

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00345

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00183 AC: 266 AN: 145028 Hom.: 0 Cov.: 0 AF XY: 0.00169 AC XY: 133 AN XY: 78804

Gnomad4 AFR exome AF: 0.000261

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000460

Gnomad4 FIN exome AF: 0.00282

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00238 AC: 34 AN: 14286 Hom.: 0 Cov.: 0 AF XY: 0.00171 AC XY: 13 AN XY: 7612

Gnomad4 AFR AF: 0.000254

Gnomad4 AMR AF: 0.000440

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00421

Gnomad4 NFE AF: 0.00474

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000246 Hom.: 0

ClinVar

Significance: Benign/Likely 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.0
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
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: rs377030217; hg19: chr16-1260360;