rs1054644

Positions:

• chr16-1220111-G-A

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.6179G>A​(p.Arg2060His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,483,932 control chromosomes in the GnomAD database, including 13,314 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2060C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.094 (920 hom., cov: 35)
  • Exomes 𝑓: 0.13 (12394 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.429

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=0.0051501095).
• BP6: Variant 16-1220111-G-A is Benign according to our data. Variant chr16-1220111-G-A is described in ClinVar as [Benign]. Clinvar id is 96015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1220111-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.6179G>A	p.Arg2060His	missense_variant	35/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6179G>A	p.Arg2060His	missense_variant	35/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14328 AN: 152106 Hom.: 922 Cov.: 35

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0952

GnomAD3 exomes AF: 0.108 AC: 14677 AN: 135794 Hom.: 1013 AF XY: 0.116 AC XY: 8581 AN XY: 74262

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0775

Gnomad EAS exome AF: 0.0216

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.0990

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.130 AC: 173665 AN: 1331708 Hom.: 12394 Cov.: 31 AF XY: 0.133 AC XY: 86695 AN XY: 651552

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.0887

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.0941 AC: 14323 AN: 152224 Hom.: 920 Cov.: 35 AF XY: 0.0944 AC XY: 7022 AN XY: 74404

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0737

Gnomad4 ASJ AF: 0.0848

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.0985

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.0947

Alfa AF: 0.107 Hom.: 444

TwinsUK AF: 0.133 AC: 493

ALSPAC AF: 0.132 AC: 510

ESP6500AA AF: 0.0218 AC: 86

ESP6500EA AF: 0.124 AC: 1025

ExAC AF: 0.106 AC: 12587

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2013

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T;T;T;.
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.90	N;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.25	T;.;T;T
Sift4G	Benign	0.081	T;.;T;T
Polyphen		0.0020	B;.;B;B
Vest4		0.043
ClinPred		0.0014	T
GERP RS		0.24
Varity_R		0.043
gMVP		0.21

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: rs1054644; hg19: chr16-1270111; COSMIC: COSV52352958; COSMIC: COSV52352958;