rs9934839

Positions:

• chr16-1202259-A-G

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.1809A>G​(p.Arg603Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,571,310 control chromosomes in the GnomAD database, including 194,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19495 hom., cov: 35)
  • Exomes 𝑓: 0.49 (174978 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.570

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=-0.73).
• BP6: Variant 16-1202259-A-G is Benign according to our data. Variant chr16-1202259-A-G is described in ClinVar as [Benign]. Clinvar id is 96003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202259-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1809A>G	p.Arg603Arg	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.1809A>G	p.Arg603Arg	synonymous_variant	9/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1809A>G	p.Arg603Arg	synonymous_variant	8/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1770A>G	p.Arg590Arg	synonymous_variant	9/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1809A>G		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1385+424A>G		intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75082 AN: 152050 Hom.: 19461 Cov.: 35

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.418 AC: 74333 AN: 177792 Hom.: 16850 AF XY: 0.419 AC XY: 40811 AN XY: 97304

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.353

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.488 AC: 692436 AN: 1419142 Hom.: 174978 Cov.: 64 AF XY: 0.483 AC XY: 339037 AN XY: 702244

Gnomad4 AFR exome AF: 0.588

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.0946

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.458

GnomAD4 genome AF: 0.494 AC: 75158 AN: 152168 Hom.: 19495 Cov.: 35 AF XY: 0.488 AC XY: 36338 AN XY: 74410

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.326

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.505

Gnomad4 OTH AF: 0.462

Alfa AF: 0.489 Hom.: 6571

Bravo AF: 0.487

Asia WGS AF: 0.254 AC: 887 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 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	GeneDx	Apr 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 01, 2021	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.1
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs9934839; hg19: chr16-1252259; COSMIC: COSV61990652; COSMIC: COSV61990652;