rs781049180

chr16-1195563-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021098.3(CACNA1H):c.543G>A(p.Ala181=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,591,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003526
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-1195563-G-A is Benign according to our data. Variant chr16-1195563-G-A is described in ClinVar as [Benign]. Clinvar id is 529625.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.7 with no splicing effect.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.543G>A	p.Ala181=	splice_region_variant, synonymous_variant	4/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.543G>A	p.Ala181=	splice_region_variant, synonymous_variant	4/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151976 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 40 AN: 209916 Hom.: 0 AF XY: 0.000159 AC XY: 18 AN XY: 113450

Gnomad AFR exome AF: 0.0000831

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000649

Gnomad SAS exome AF: 0.0000763

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000820 AC: 118 AN: 1439284 Hom.: 0 Cov.: 34 AF XY: 0.0000925 AC XY: 66 AN XY: 713802

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000849

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000408

Gnomad4 OTH exome AF: 0.000303

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151976 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74206

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000144

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.080
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0040
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: rs781049180; hg19: chr16-1245563;