rs370079169

Positions:

• chr16-1213792-G-A
• chr16-1213792-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021098.3(CACNA1H):​c.4790G>A​(p.Arg1597Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,563,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1597G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.18

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013262987).
• BP6: Variant 16-1213792-G-A is Benign according to our data. Variant chr16-1213792-G-A is described in ClinVar as [Benign]. Clinvar id is 529681.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.4790G>A	p.Arg1597Gln	missense_variant	27/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4790G>A	p.Arg1597Gln	missense_variant	27/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000369 AC: 64 AN: 173394 Hom.: 0 AF XY: 0.000417 AC XY: 39 AN XY: 93452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 237 AN: 1411470 Hom.: 0 Cov.: 31 AF XY: 0.000182 AC XY: 127 AN XY: 698010

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.0000539

Gnomad4 ASJ exome AF: 0.00473

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000753

Gnomad4 OTH exome AF: 0.000443

GnomAD4 genome AF: 0.000263 AC: 40 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74240

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000724 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000280 AC: 33

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CACNA1H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.95	D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.20	T;.;T;T
Sift4G	Benign	0.26	T;.;T;T
Polyphen		0.99	D;.;D;D
Vest4		0.62
MVP		0.89
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.59

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: rs370079169; hg19: chr16-1263792;