rs9922076

Positions:

• chr16-1201803-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.1353C>T​(p.Ser451Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,590,818 control chromosomes in the GnomAD database, including 14,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (978 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13033 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.54

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]

CACNA1H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-1201803-C-T is Benign according to our data. Variant chr16-1201803-C-T is described in ClinVar as [Benign]. Clinvar id is 96000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1201803-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1353C>T	p.Ser451Ser	synonymous_variant	9/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1353C>T	p.Ser451Ser	synonymous_variant	9/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1353C>T	p.Ser451Ser	synonymous_variant	8/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1314C>T	p.Ser438Ser	synonymous_variant	9/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1353C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1353C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15371 AN: 152176 Hom.: 976 Cov.: 34

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.117 AC: 24578 AN: 209934 Hom.: 1608 AF XY: 0.123 AC XY: 13973 AN XY: 113812

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.0680

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.131 AC: 188797 AN: 1438524 Hom.: 13033 Cov.: 36 AF XY: 0.132 AC XY: 94446 AN XY: 713418

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0740

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.101 AC: 15366 AN: 152294 Hom.: 978 Cov.: 34 AF XY: 0.102 AC XY: 7603 AN XY: 74452

Gnomad4 AFR AF: 0.0381

Gnomad4 AMR AF: 0.0855

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.0631

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.112

Alfa AF: 0.117 Hom.: 548

Bravo AF: 0.0925

Asia WGS AF: 0.112 AC: 391 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.055
DANN	Benign	0.94

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: rs9922076; hg19: chr16-1251803; COSMIC: COSV61990621; COSMIC: COSV61990621;