rs201352768

chr16-1210449-G-A

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.3925G>A(p.Val1309Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000549 in 1,611,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1309F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.33

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=0.030431986).
• BP6: Variant 16-1210449-G-A is Benign according to our data. Variant chr16-1210449-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 570660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1210449-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000343 (52/151532) while in subpopulation NFE AF= 0.000633 (43/67910). AF 95% confidence interval is 0.000482. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.3925G>A	p.Val1309Ile	missense_variant	19/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3925G>A	p.Val1309Ile	missense_variant	19/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000343 AC: 52 AN: 151532 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000286

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000461 AC: 114 AN: 247246 Hom.: 0 AF XY: 0.000490 AC XY: 66 AN XY: 134746

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000804

Gnomad NFE exome AF: 0.000805

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.000571 AC: 833 AN: 1459848 Hom.: 0 Cov.: 38 AF XY: 0.000580 AC XY: 421 AN XY: 726260

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000886

Gnomad4 NFE exome AF: 0.000683

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000343 AC: 52 AN: 151532 Hom.: 0 Cov.: 27 AF XY: 0.000325 AC XY: 24 AN XY: 73908

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000286

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000441 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000421 AC: 51

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 10, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	13
Dann	Benign	0.92
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T;T;T;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-2.6	N;.;N;N
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.84	N;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.12
MVP		0.53
ClinPred		0.012	T
GERP RS		2.7
Varity_R		0.052
gMVP		0.31

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: rs201352768; hg19: chr16-1260449; COSMIC: COSV61992106; COSMIC: COSV61992106;