rs756154211

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_021098.3(CACNA1H):c.3643C>T(p.Arg1215Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,596,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. R1215H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.83

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38686275).

BP6

Variant 16-1209311-C-T is Benign according to our data. Variant chr16-1209311-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 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.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3604C>T	p.Arg1202Cys	missense_variant	Exon 17 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3604C>T	p.Arg1202Cys	missense_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3643C>T	p.Arg1215Cys	missense_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1556C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3090C>T		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3643C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1556C>T		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3090C>T		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000535

AC:

AN:

224194

AF XY:

0.0000481

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000512

AC:

AN:

1444252

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

718812

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33400

American (AMR)

AF:

0.000180

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1110488

Other (OTH)

AF:

0.0000832

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41576

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000514

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 24, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1H c.3643C>T (p.Arg1215Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 224194 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1H causing Idiopathic Generalized Epilepsy, allowing no conclusion about variant significance. c.3643C>T has been reported in the literature in one individual affected with Hemiplegic migraine (Maksemous_2023). The report does not provide unequivocal conclusions about association of the variant with Idiopathic Generalized Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36786913). ClinVar contains an entry for this variant (Variation ID: 529594). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Epilepsy, childhood absence, susceptibility to, 6

Uncertain:1

May 14, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jul 02, 2024

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

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.82

T;T;T;.

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.9

L;.;L;L

PhyloP100

2.8

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0080

D;.;D;D

Sift4G

Uncertain

0.050

T;.;D;D

Polyphen

0.95

P;.;D;D

Vest4

0.25

MutPred

0.32

Loss of solvent accessibility (P = 6e-04);.;Loss of solvent accessibility (P = 6e-04);Loss of solvent accessibility (P = 6e-04);

MVP

0.81

ClinPred

0.85

GERP RS

4.0

Varity_R

0.12

gMVP

0.57

Mutation Taster

=89/11

polymorphism

(source)

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

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rs756154211

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over