rs58535913

Positions:

• chr16-1220866-A-G
• chr16-1220866-A-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.6934A>G​(p.Met2312Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,612,560 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0470

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=0.006071508).
• BP6: Variant 16-1220866-A-G is Benign according to our data. Variant chr16-1220866-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 460180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00161 (245/152078) while in subpopulation NFE AF= 0.00184 (125/67952). AF 95% confidence interval is 0.00158. There are 3 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 245 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.6934A>G	p.Met2312Val	missense_variant	35/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6934A>G	p.Met2312Val	missense_variant	35/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 151962 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00158 AC: 392 AN: 248466 Hom.: 1 AF XY: 0.00159 AC XY: 215 AN XY: 135098

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00835

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00128 AC: 1876 AN: 1460482 Hom.: 7 Cov.: 34 AF XY: 0.00127 AC XY: 925 AN XY: 726540

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00978

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152078 Hom.: 3 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74372

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00848

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000816 AC: 3

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CACNA1H: BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.0040
DANN	Benign	0.45
DEOGEN2	Benign	0.087	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.45	T;T;T;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-0.34	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.10	N;.;N;N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.62	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.054
MVP		0.73
ClinPred		0.0044	T
GERP RS		-6.1
Varity_R		0.10
gMVP		0.060

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: rs58535913; hg19: chr16-1270866;