16-1202114-C-T

Position:

chr16-1202114-C-T

Variant summary

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

The NM_021098.3(CACNA1H):c.1664C>T(p.Ala555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,546,262 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 9 hom., cov: 34)

Exomes 𝑓: 0.015 ( 180 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021456778).

BP6

Variant 16-1202114-C-T is Benign according to our data. Variant chr16-1202114-C-T is described in ClinVar as [Benign]. Clinvar id is 96001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1202114-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2208/152338) while in subpopulation NFE AF= 0.0166 (1132/68016). AF 95% confidence interval is 0.0158. There are 9 homozygotes in gnomad4. There are 1033 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2208 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.1664C>T	p.Ala555Val	missense_variant	9/35	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.1664C>T	p.Ala555Val	missense_variant	9/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.1664C>T	p.Ala555Val	missense_variant	8/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.1625C>T	p.Ala542Val	missense_variant	9/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.1664C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.1385+279C>T		intron_variant		5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2206

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.0111

AC:

1547

AN:

139104

Hom.:

AF XY:

0.0108

AC XY:

817

AN XY:

75476

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.00849

Gnomad ASJ exome

AF:

0.00959

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000536

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0154

AC:

21496

AN:

1393924

Hom.:

180

Cov.:

AF XY:

0.0149

AC XY:

10270

AN XY:

687418

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.00842

Gnomad4 ASJ exome

AF:

0.00928

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000543

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.0175

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0145

AC:

2208

AN:

152338

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1033

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0166

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0148

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00958

AC:

ESP6500EA

AF:

0.0162

AC:

ExAC

AF:

0.00573

AC:

429

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2013

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.21

DANN

Benign

0.90

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.19

T;T;T;.

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.42

N;.;N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.18

N;.;N;N

REVEL

Benign

0.16

Sift

Benign

0.48

T;.;T;T

Sift4G

Benign

0.55

T;.;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.077

ClinPred

0.00092

GERP RS

-2.5

Varity_R

0.042

gMVP

0.29

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