rs28365117

chr16-1204361-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.2354A>T(p.Lys785Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,576,242 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (21 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.97

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=0.03796467).
• BP6: Variant 16-1204361-A-T is Benign according to our data. Variant chr16-1204361-A-T is described in ClinVar as [Benign]. Clinvar id is 460063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1204361-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00295 (449/152370) while in subpopulation AMR AF= 0.0049 (75/15312). AF 95% confidence interval is 0.00401. There are 2 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 449 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.2354A>T	p.Lys785Met	missense_variant	10/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2354A>T	p.Lys785Met	missense_variant	10/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152252 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00357 AC: 774 AN: 216636 Hom.: 3 AF XY: 0.00362 AC XY: 424 AN XY: 117272

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.000862

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00509

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00389 AC: 5537 AN: 1423872 Hom.: 21 Cov.: 32 AF XY: 0.00397 AC XY: 2794 AN XY: 704212

Gnomad4 AFR exome AF: 0.000460

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.000851

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152370 Hom.: 2 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74520

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00294

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.00331 AC: 28

ExAC AF: 0.00358 AC: 430

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CACNA1H: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2018	- -
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	-	- -

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	0.31
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M;.;M;M
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;.;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.014	D;.;D;D
Sift4G	Uncertain	0.019	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.72
MVP		0.97
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.66

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: rs28365117; hg19: chr16-1254361; COSMIC: COSV62005812; COSMIC: COSV62005812;