rs552269381

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_021098.3(CACNA1H):c.3742G>A(p.Asp1248Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,597,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D1248D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense, splice_region

Scores

Splicing: ADA: 0.01299

Clinical Significance

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

Conservation

PhyloP100: 3.44

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.114195734).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000177 (27/152362) while in subpopulation AFR AF = 0.000649 (27/41590). AF 95% confidence interval is 0.000458. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_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.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3703G>A	p.Asp1235Asn	missense_variant, splice_region_variant	Exon 17 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3703G>A	p.Asp1235Asn	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3742G>A	p.Asp1248Asn	missense_variant, splice_region_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3742G>A		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1655G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3189G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3742G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1655G>A		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3189G>A		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000479

AC:

AN:

229590

AF XY:

0.0000394

show subpopulations

Gnomad AFR exome

AF:

0.000720

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:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1444874

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

719134

show subpopulations

African (AFR)

AF:

0.000630

AC:

AN:

33310

American (AMR)

AF:

0.0000224

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37880

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111212

Other (OTH)

AF:

0.0000498

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000177

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.0000589

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Apr 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3742G>A (p.D1248N) alteration is located in exon 17 (coding exon 16) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 3742, causing the aspartic acid (D) at amino acid position 1248 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1248 of the CACNA1H protein (p.Asp1248Asn). This variant is present in population databases (rs552269381, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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: 460097). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

0.091

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T;T;.

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.;M;M

PhyloP100

3.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.88

N;.;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.42

T;.;T;T

Sift4G

Benign

0.51

T;.;T;T

Polyphen

0.99

D;.;D;D

Vest4

0.48

MutPred

0.37

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

MVP

0.92

ClinPred

0.11

GERP RS

3.5

Varity_R

0.090

gMVP

0.46

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.013

dbscSNV1_RF

Benign

0.25

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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rs552269381

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over