NM_021098.3:c.2030C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_021098.3(CACNA1H):c.2030C>G(p.Ser677Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,418,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S677L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.19

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 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.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1991C>G	p.Ser664Trp	missense_variant	Exon 10 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1991C>G	p.Ser664Trp	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2030C>G	p.Ser677Trp	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1413C>G		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*1477C>G		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2030C>G		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*1477C>G		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1418566

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

701814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32444

American (AMR)

AF:

0.00

AC:

AN:

39524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37300

South Asian (SAS)

AF:

0.00

AC:

AN:

81256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090942

Other (OTH)

AF:

0.0000170

AC:

AN:

58794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;.

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.7

M;.;M;M

PhyloP100

7.2

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0050

D;.;D;D

Sift4G

Uncertain

0.015

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.64

MutPred

0.36

Loss of disorder (P = 3e-04);.;Loss of disorder (P = 3e-04);Loss of disorder (P = 3e-04);

MVP

0.97

ClinPred

0.98

GERP RS

4.3

Varity_R

0.46

gMVP

0.61

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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NM_021098.3:c.2030C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over