rs747200195

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021098.3(CACNA1H):c.3744C>G(p.Asp1248Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D1248N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense, splice_region

Scores

Splicing: ADA: 0.00002241

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.547

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1354649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.3705C>G	p.Asp1235Glu	missense_variant, splice_region_variant	Exon 17 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.3705C>G	p.Asp1235Glu	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3744C>G		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1657C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3191C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1657C>G		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3191C>G		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444546

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33254

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111040

Other (OTH)

AF:

0.00

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

0.0087

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.2

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.091

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.71

T;T;T;.

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.5

L;.;L;L

PhyloP100

-0.55

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.61

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

1.0

D;.;P;P

Vest4

0.44

MutPred

0.33

Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.86

ClinPred

0.16

GERP RS

-5.8

Varity_R

0.040

gMVP

0.36

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over