rs2407083

Positions:

• chr16-1202118-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.1668C>T​(p.Pro556Pro) 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 1,546,556 control chromosomes in the GnomAD database, including 13,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (982 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12616 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.57

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=-0.79).
• BP6: Variant 16-1202118-C-T is Benign according to our data. Variant chr16-1202118-C-T is described in ClinVar as [Benign]. Clinvar id is 96002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202118-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1668C>T	p.Pro556Pro	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.1668C>T	p.Pro556Pro	synonymous_variant	9/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1668C>T	p.Pro556Pro	synonymous_variant	8/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1629C>T	p.Pro543Pro	synonymous_variant	9/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1668C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1385+283C>T		intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15373 AN: 152178 Hom.: 980 Cov.: 34

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.115 AC: 16038 AN: 140046 Hom.: 1065 AF XY: 0.121 AC XY: 9197 AN XY: 75964

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.0587

Gnomad ASJ exome AF: 0.0739

Gnomad EAS exome AF: 0.0691

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.131 AC: 182907 AN: 1394260 Hom.: 12616 Cov.: 36 AF XY: 0.132 AC XY: 91019 AN XY: 687576

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.0619

Gnomad4 ASJ exome AF: 0.0733

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.101 AC: 15369 AN: 152296 Hom.: 982 Cov.: 34 AF XY: 0.103 AC XY: 7634 AN XY: 74468

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.0846

Gnomad4 ASJ AF: 0.0625

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.110

Alfa AF: 0.120 Hom.: 383

Bravo AF: 0.0918

Asia WGS AF: 0.111 AC: 388 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	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Athena Diagnostics	Apr 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
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	-0.79
CADD	Benign	0.62
DANN	Benign	0.80

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: rs2407083; hg19: chr16-1252118; COSMIC: COSV61986592; COSMIC: COSV61986592;