16-1208189-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021098.3(CACNA1H):c.3331G>C(p.Gly1111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,550,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1111G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.331

Publications

5 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=0.10555413).

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 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.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3292G>C	p.Gly1098Arg	missense_variant	Exon 16 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3292G>C	p.Gly1098Arg	missense_variant	Exon 16 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3331G>C	p.Gly1111Arg	missense_variant	Exon 16 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1244G>C		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2778G>C		non_coding_transcript_exon_variant	Exon 15 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3331G>C		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1244G>C		3_prime_UTR_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2778G>C		3_prime_UTR_variant	Exon 15 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000397

AC:

AN:

151142

AF XY:

0.0000608

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1398290

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

690702

show subpopulations

African (AFR)

AF:

0.000284

AC:

AN:

31644

American (AMR)

AF:

0.00

AC:

AN:

36280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

35952

South Asian (SAS)

AF:

0.000151

AC:

AN:

79624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4320

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081814

Other (OTH)

AF:

0.00

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41524

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000955

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1111 of the CACNA1H protein (p.Gly1111Arg). This variant is present in population databases (rs59529743, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 572432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Apr 23, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.30

CADD

Benign

6.0

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.091

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.75

T;T;T;.

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.0

N;.;N;N

PhyloP100

-0.33

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Benign

0.14

Sift

Benign

0.35

T;.;T;T

Sift4G

Benign

0.51

T;.;T;T

Polyphen

0.39

B;.;B;B

Vest4

0.21

MutPred

0.28

Gain of solvent accessibility (P = 0.019);.;Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);

MVP

0.64

ClinPred

0.018

GERP RS

-1.8

Varity_R

0.063

gMVP

0.44

Mutation Taster

=100/0

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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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