rs60593994

chr16-1195509-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.489G>C(p.Gln163His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,602,790 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (52 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.63

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=0.009828389).
• BP6: Variant 16-1195509-G-C is Benign according to our data. Variant chr16-1195509-G-C is described in ClinVar as [Benign]. Clinvar id is 460131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195509-G-C is described in Lovd as [Benign]. Variant chr16-1195509-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00363 (552/152246) while in subpopulation SAS AF= 0.0162 (78/4826). AF 95% confidence interval is 0.0133. There are 5 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.489G>C	p.Gln163His	missense_variant	4/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.489G>C	p.Gln163His	missense_variant	4/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 553 AN: 152128 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00490 AC: 1126 AN: 229966 Hom.: 12 AF XY: 0.00593 AC XY: 738 AN XY: 124368

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.0000595

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.00547

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00610

GnomAD4 exome AF: 0.00406 AC: 5888 AN: 1450544 Hom.: 52 Cov.: 34 AF XY: 0.00453 AC XY: 3266 AN XY: 720216

Gnomad4 AFR exome AF: 0.000781

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.00523

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00363 AC: 552 AN: 152246 Hom.: 5 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74450

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.00427

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00471 Hom.: 3

Bravo AF: 0.00264

ESP6500AA AF: 0.000492 AC: 2

ESP6500EA AF: 0.00228 AC: 19

ExAC AF: 0.00472 AC: 569

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2020	This variant is associated with the following publications: (PMID: 30686625, 32227660) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Epilepsy, childhood absence, susceptibility to, 6 Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D;D;D;.
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.76	N;.;N;N
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;.;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.061	T;.;T;T
Sift4G	Uncertain	0.028	D;.;D;D
Polyphen		0.051	B;.;D;D
Vest4		0.49
MutPred		0.49		Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.91
ClinPred		0.012	T
GERP RS		2.7
Varity_R		0.33
gMVP		0.61

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: rs60593994; hg19: chr16-1245509; COSMIC: COSV61989280;