rs372000875

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):c.3757C>A(p.Arg1253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,550,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1253L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.24

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 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.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3718C>A	p.Arg1240Ser	missense_variant	Exon 18 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3718C>A	p.Arg1240Ser	missense_variant	Exon 18 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3757C>A	p.Arg1253Ser	missense_variant	Exon 18 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3807C>A		non_coding_transcript_exon_variant	Exon 18 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1670C>A		non_coding_transcript_exon_variant	Exon 18 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3204C>A		non_coding_transcript_exon_variant	Exon 17 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3757C>A		non_coding_transcript_exon_variant	Exon 18 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1670C>A		3_prime_UTR_variant	Exon 18 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3204C>A		3_prime_UTR_variant	Exon 17 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153628

AF XY:

0.0000122

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000338

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000357

AC:

AN:

1398742

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31626

American (AMR)

AF:

0.00

AC:

AN:

35980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

35828

South Asian (SAS)

AF:

0.00

AC:

AN:

79292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1079736

Other (OTH)

AF:

0.00

AC:

AN:

58014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000164

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000959

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;.

Eigen

Benign

-0.030

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.83

T;T;T;.

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.0

M;.;M;M

PhyloP100

1.2

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.0

D;.;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0030

D;.;D;D

Sift4G

Uncertain

0.011

D;.;D;D

Polyphen

0.99

D;.;D;D

Vest4

0.72

MutPred

0.45

Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.93

ClinPred

0.96

GERP RS

1.7

PromoterAI

-0.0039

Neutral

(source)

Varity_R

0.60

gMVP

0.81

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over