rs746967306

chr16-1218616-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_021098.3(CACNA1H):c.5852T>A(p.Val1951Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,555,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.583

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12965441).
• BP6: Variant 16-1218616-T-A is Benign according to our data. Variant chr16-1218616-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 578030.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5852T>A	p.Val1951Glu	missense_variant	33/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5852T>A	p.Val1951Glu	missense_variant	33/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000680 AC: 10 AN: 147006 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

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: 0.0000897

Gnomad OTH AF: 0.000496

GnomAD3 exomes AF: 0.0000999 AC: 17 AN: 170152 Hom.: 0 AF XY: 0.0000984 AC XY: 9 AN XY: 91450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000766

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000216

GnomAD4 exome AF: 0.0000681 AC: 96 AN: 1408846 Hom.: 0 Cov.: 38 AF XY: 0.0000690 AC XY: 48 AN XY: 695788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000329

Gnomad4 NFE exome AF: 0.0000636

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.0000680 AC: 10 AN: 147100 Hom.: 0 Cov.: 30 AF XY: 0.0000699 AC XY: 5 AN XY: 71524

Gnomad4 AFR AF: 0.0000254

Gnomad4 AMR AF: 0.000135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000897

Gnomad4 OTH AF: 0.000491

Alfa AF: 0.0000822 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000342 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.20	T;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.63	T;.;T;T
Sift4G	Benign	0.84	T;.;T;T
Polyphen		0.93	P;.;P;P
Vest4		0.60
MVP		0.93
ClinPred		0.13	T
GERP RS		2.3
Varity_R		0.38
gMVP		0.44

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: rs746967306; hg19: chr16-1268616;