rs148651456

chr16-1215315-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.5113G>A(p.Ala1705Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,611,068 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1705A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (37 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.78

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=0.011093318).
• BP6: Variant 16-1215315-G-A is Benign according to our data. Variant chr16-1215315-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1215315-G-A is described in Lovd as [Benign]. Variant chr16-1215315-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0057 (869/152328) while in subpopulation NFE AF= 0.00858 (584/68026). AF 95% confidence interval is 0.00801. There are 5 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 868 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.5113G>A	p.Ala1705Thr	missense_variant	29/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5113G>A	p.Ala1705Thr	missense_variant	29/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 868 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00556 AC: 1356 AN: 243960 Hom.: 6 AF XY: 0.00551 AC XY: 731 AN XY: 132768

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.00871

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.000300

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00941

GnomAD4 exome AF: 0.00731 AC: 10664 AN: 1458740 Hom.: 37 Cov.: 33 AF XY: 0.00711 AC XY: 5161 AN XY: 725390

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.00891

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000280

Gnomad4 FIN exome AF: 0.00595

Gnomad4 NFE exome AF: 0.00844

Gnomad4 OTH exome AF: 0.00718

GnomAD4 genome AF: 0.00570 AC: 869 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00502 AC XY: 374 AN XY: 74486

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00858

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00750 Hom.: 6

Bravo AF: 0.00630

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00161 AC: 7

ESP6500EA AF: 0.00925 AC: 79

ExAC AF: 0.00554 AC: 670

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1H: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 31, 2023

- -

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	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;.;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.060	T;.;T;T
Sift4G	Uncertain	0.039	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.64
MVP		0.95
ClinPred		0.022	T
GERP RS		4.0
Varity_R		0.32
gMVP		0.69

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: rs148651456; hg19: chr16-1265315; COSMIC: COSV61986372; COSMIC: COSV61986372;