chr16-1195509-G-C

Position:

chr16-1195509-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.489G>C(p.Gln163His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,602,790 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 52 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.63

Variant links:

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]

CACNA1H links:

CACNA1H (HGNC:):

CACNA1H links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009828389).

BP6

Variant 16-1195509-G-C is Benign according to our data. Variant chr16-1195509-G-C is described in ClinVar as [Benign]. Clinvar id is 460131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195509-G-C is described in Lovd as [Benign]. Variant chr16-1195509-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00363 (552/152246) while in subpopulation SAS AF= 0.0162 (78/4826). AF 95% confidence interval is 0.0133. There are 5 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 552 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.489G>C	p.Gln163His	missense_variant	4/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.489G>C	p.Gln163His	missense_variant	4/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.489G>C	p.Gln163His	missense_variant	3/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.450G>C	p.Gln150His	missense_variant	4/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.489G>C		non_coding_transcript_exon_variant	4/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.489G>C		non_coding_transcript_exon_variant	4/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

553

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.00763

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00490

AC:

1126

AN:

229966

Hom.:

AF XY:

0.00593

AC XY:

738

AN XY:

124368

show subpopulations

Gnomad AFR exome

AF:

0.000583

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.0000595

Gnomad SAS exome

AF:

0.0168

Gnomad FIN exome

AF:

0.00547

Gnomad NFE exome

AF:

0.00378

Gnomad OTH exome

AF:

0.00610

GnomAD4 exome

AF:

0.00406

AC:

5888

AN:

1450544

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

3266

AN XY:

720216

show subpopulations

Gnomad4 AFR exome

AF:

0.000781

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.00459

Gnomad4 EAS exome

AF:

0.0000510

Gnomad4 SAS exome

AF:

0.0170

Gnomad4 FIN exome

AF:

0.00523

Gnomad4 NFE exome

AF:

0.00319

Gnomad4 OTH exome

AF:

0.00477

GnomAD4 genome

AF:

0.00363

AC:

552

AN:

152246

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.00763

Gnomad4 NFE

AF:

0.00427

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00471

Hom.:

Bravo

AF:

0.00264

ESP6500AA

AF:

0.000492

AC:

ESP6500EA

AF:

0.00228

AC:

ExAC

AF:

0.00472

AC:

569

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2020	This variant is associated with the following publications: (PMID: 30686625, 32227660) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Epilepsy, childhood absence, susceptibility to, 6

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;.

Eigen

Benign

-0.093

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.87

D;D;D;.

MetaRNN

Benign

0.0098

T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.76

N;.;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

N;.;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.061

T;.;T;T

Sift4G

Uncertain

0.028

D;.;D;D

Polyphen

0.051

B;.;D;D

Vest4

0.49

MutPred

0.49

Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.91

ClinPred

0.012

GERP RS

2.7

Varity_R

0.33

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over