rs59935412

chr16-1218604-C-T

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.5840C>T(p.Pro1947Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,565,184 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1947P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.42

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=0.006367117).
• BP6: Variant 16-1218604-C-T is Benign according to our data. Variant chr16-1218604-C-T is described in ClinVar as [Benign]. Clinvar id is 460154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00561 (853/152074) while in subpopulation AFR AF= 0.0192 (795/41474). AF 95% confidence interval is 0.0181. There are 11 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5840C>T	p.Pro1947Leu	missense_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5840C>T	p.Pro1947Leu	missense_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 851 AN: 151956 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00125 AC: 219 AN: 175698 Hom.: 3 AF XY: 0.000868 AC XY: 82 AN XY: 94504

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000420

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000549

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.000534 AC: 754 AN: 1413110 Hom.: 4 Cov.: 38 AF XY: 0.000462 AC XY: 323 AN XY: 698412

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000498

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000313

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00561 AC: 853 AN: 152074 Hom.: 11 Cov.: 31 AF XY: 0.00541 AC XY: 402 AN XY: 74328

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00262 Hom.: 2

Bravo AF: 0.00652

ESP6500AA AF: 0.0131 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 147

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D;D;D;.
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.084	T;.;T;T
Sift4G	Benign	0.22	T;.;T;T
Polyphen		0.013	B;.;B;B
Vest4		0.38
MVP		0.84
ClinPred		0.0092	T
GERP RS		-0.34
Varity_R		0.090
gMVP		0.52

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: rs59935412; hg19: chr16-1268604; COSMIC: COSV52354042; COSMIC: COSV52354042;