rs201855332

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_021098.3(CACNA1H):c.4120G>A(p.Val1374Met) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,605,478 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.60

Publications

2 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 -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000354 (515/1453218) while in subpopulation AMR AF = 0.000559 (25/44716). AF 95% confidence interval is 0.000395. There are 2 homozygotes in GnomAdExome4. There are 227 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. 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.4120G>A	p.Val1374Met	missense_variant	Exon 21 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.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4081G>A	p.Val1361Met	missense_variant	Exon 21 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4081G>A	p.Val1361Met	missense_variant	Exon 21 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4120G>A	p.Val1374Met	missense_variant	Exon 21 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*90G>A		non_coding_transcript_exon_variant	Exon 21 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2033G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3567G>A		non_coding_transcript_exon_variant	Exon 20 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4120G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*90G>A		3_prime_UTR_variant	Exon 21 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2033G>A		3_prime_UTR_variant	Exon 21 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3567G>A		3_prime_UTR_variant	Exon 20 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000279

AC:

AN:

243392

AF XY:

0.000218

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000357

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000354

AC:

515

AN:

1453218

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

227

AN XY:

723292

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.000559

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.000427

AC:

475

AN:

1111686

Other (OTH)

AF:

0.000216

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000177

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000749

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jul 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1H c.4120G>A (p.Val1374Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 243392 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4120G>A in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jul 10, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1374 of the CACNA1H protein (p.Val1374Met). This variant is present in population databases (rs201855332, gnomAD 0.06%), 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: 446952). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1H protein function with a positive 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;.;M;M

PhyloP100

6.6

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

N;.;N;N

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.0030

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.71

MVP

0.94

ClinPred

0.22

GERP RS

4.2

Varity_R

0.66

gMVP

0.82

Mutation Taster

=25/75

disease causing

(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