rs577235589

chr16-1154007-C-Gchr16-1154007-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):c.270C>G(p.Arg90=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,404,994 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R90R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0041 (79 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0260

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 16-1154007-C-G is Benign according to our data. Variant chr16-1154007-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 460071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1154007-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.026 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00353 (526/148996) while in subpopulation SAS AF= 0.0313 (146/4672). AF 95% confidence interval is 0.0271. There are 8 homozygotes in gnomad4. There are 297 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.270C>G	p.Arg90=	synonymous_variant	2/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.270C>G	p.Arg90=	synonymous_variant	2/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 527 AN: 148924 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.000470

Gnomad AMI AF: 0.00996

Gnomad AMR AF: 0.00154

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.00827

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.00389

GnomAD3 exomes AF: 0.00962 AC: 695 AN: 72236 Hom.: 16 AF XY: 0.0126 AC XY: 528 AN XY: 41978

Gnomad AFR exome AF: 0.000843

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.000471

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0330

Gnomad FIN exome AF: 0.00666

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00942

GnomAD4 exome AF: 0.00407 AC: 5118 AN: 1255998 Hom.: 79 Cov.: 32 AF XY: 0.00500 AC XY: 3092 AN XY: 618446

Gnomad4 AFR exome AF: 0.000315

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000284

Gnomad4 EAS exome AF: 0.0000381

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.00549

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.00353 AC: 526 AN: 148996 Hom.: 8 Cov.: 30 AF XY: 0.00409 AC XY: 297 AN XY: 72638

Gnomad4 AFR AF: 0.000468

Gnomad4 AMR AF: 0.00154

Gnomad4 ASJ AF: 0.000581

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.00827

Gnomad4 NFE AF: 0.00349

Gnomad4 OTH AF: 0.00338

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00213

Asia WGS AF: 0.00850 AC: 28 AN: 3306

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 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2020	- -

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

Aug 04, 2021

- -

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	-0.60
Cadd	Benign	14
Dann	Benign	0.73

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: rs577235589; hg19: chr16-1204007;