rs58124832

Positions:

• chr16-1218376-G-A
• chr16-1218376-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.5612G>A​(p.Arg1871Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,561,046 control chromosomes in the GnomAD database, including 3,036 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1871W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (230 hom., cov: 34)
  • Exomes 𝑓: 0.059 (2806 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018953979).
• BP6: Variant 16-1218376-G-A is Benign according to our data. Variant chr16-1218376-G-A is described in ClinVar as [Benign]. Clinvar id is 585651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218376-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5612G>A	p.Arg1871Gln	missense_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5612G>A	p.Arg1871Gln	missense_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0451 AC: 6863 AN: 152190 Hom.: 229 Cov.: 34

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0400

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0548 AC: 9431 AN: 172182 Hom.: 337 AF XY: 0.0588 AC XY: 5378 AN XY: 91508

Gnomad AFR exome AF: 0.00844

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.0870

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0868

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0586 AC: 82512 AN: 1408738 Hom.: 2806 Cov.: 33 AF XY: 0.0597 AC XY: 41527 AN XY: 695890

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.0878

Gnomad4 EAS exome AF: 0.000192

Gnomad4 SAS exome AF: 0.0840

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0607

Gnomad4 OTH exome AF: 0.0580

GnomAD4 genome AF: 0.0451 AC: 6865 AN: 152308 Hom.: 230 Cov.: 34 AF XY: 0.0438 AC XY: 3259 AN XY: 74474

Gnomad4 AFR AF: 0.00912

Gnomad4 AMR AF: 0.0400

Gnomad4 ASJ AF: 0.0838

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0785

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0645

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0599 Hom.: 294

Bravo AF: 0.0400

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.00853 AC: 36

ESP6500EA AF: 0.0583 AC: 489

ExAC AF: 0.0410 AC: 4646

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	This variant is associated with the following publications: (PMID: 28933792) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.090	T;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.73	T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.63	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.49	T;.;T;T
Sift4G	Benign	0.89	T;.;T;T
Polyphen		0.16	B;.;B;B
Vest4		0.24
ClinPred		0.0021	T
GERP RS		1.0
Varity_R		0.068
gMVP		0.37

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: rs58124832; hg19: chr16-1268376; COSMIC: COSV52357919; COSMIC: COSV52357919;