16-1219095-C-T

Position:

• chr16-1219095-C-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.6013C>T​(p.Arg2005Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0595 in 1,547,162 control chromosomes in the GnomAD database, including 3,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (245 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2971 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.198

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=0.0018978119).
• BP6: Variant 16-1219095-C-T is Benign according to our data. Variant chr16-1219095-C-T is described in ClinVar as [Benign]. Clinvar id is 585654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1219095-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6013C>T	p.Arg2005Cys	missense_variant	34/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6013C>T	p.Arg2005Cys	missense_variant	34/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7149 AN: 152178 Hom.: 244 Cov.: 33

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0787

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0566 AC: 8457 AN: 149494 Hom.: 321 AF XY: 0.0607 AC XY: 4854 AN XY: 79906

Gnomad AFR exome AF: 0.00750

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.0954

Gnomad EAS exome AF: 0.000186

Gnomad SAS exome AF: 0.0882

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0609 AC: 84965 AN: 1394866 Hom.: 2971 Cov.: 35 AF XY: 0.0620 AC XY: 42610 AN XY: 687636

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0944

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.0851

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0631

Gnomad4 OTH exome AF: 0.0609

GnomAD4 genome AF: 0.0470 AC: 7151 AN: 152296 Hom.: 245 Cov.: 33 AF XY: 0.0455 AC XY: 3391 AN XY: 74462

Gnomad4 AFR AF: 0.00941

Gnomad4 AMR AF: 0.0436

Gnomad4 ASJ AF: 0.0910

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0794

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0672

Gnomad4 OTH AF: 0.0568

Alfa AF: 0.0581 Hom.: 201

Bravo AF: 0.0420

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.00739 AC: 25

ESP6500EA AF: 0.0536 AC: 389

ExAC AF: 0.0289 AC: 2059

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2020	This variant is associated with the following publications: (PMID: 17696120, 28933792, 29588962) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	8.9
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.72	T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	D;.;D;D
REVEL	Benign	0.26
Sift	Benign	0.052	T;.;T;T
Sift4G	Uncertain	0.043	D;.;D;D
Polyphen		0.0010	B;.;B;B
Vest4		0.12
ClinPred		0.029	T
GERP RS		-1.9
Varity_R		0.17
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72552056; hg19: chr16-1269095; COSMIC: COSV52359202; COSMIC: COSV52359202;