rs761083620

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_021098.3(CACNA1H):c.6652C>T(p.Arg2218Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,543,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2218H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.848

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 16-1220584-C-T is Benign according to our data. Variant chr16-1220584-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571712.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6652C>T	p.Arg2218Cys	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.6652C>T	p.Arg2218Cys	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.6634C>T	p.Arg2212Cys	missense_variant	Exon 33 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.6613C>T	p.Arg2205Cys	missense_variant	Exon 35 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.2890C>T	p.Arg964Cys	missense_variant	Exon 17 of 17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.2842C>T	p.Arg948Cys	missense_variant	Exon 18 of 18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.2824C>T	p.Arg942Cys	missense_variant	Exon 17 of 17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 link	n.*1700C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4470C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 link	n.*1700C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4470C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000114

AC:

AN:

176190

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

97176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000120

Gnomad OTH exome

AF:

0.000243

GnomAD4 exome

AF:

0.0000331

AC:

AN:

1391058

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

686834

show subpopulations

Gnomad4 AFR exome

AF:

0.0000326

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000388

Gnomad4 OTH exome

AF:

0.0000525

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151950

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000875

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000853

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6652C>T (p.R2218C) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 6652, causing the arginine (R) at amino acid position 2218 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.95

D;D;D;.

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.0

M;.;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.7

D;.;D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.44

MutPred

0.32

Loss of solvent accessibility (P = 0.0079);.;.;.;

MVP

0.82

ClinPred

0.98

GERP RS

2.7

Varity_R

0.22

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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