rs58386301

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.817A>T(p.Thr273Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,600,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T273I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.94

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012571752).

BP6

Variant 16-1200269-A-T is Benign according to our data. Variant chr16-1200269-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 460190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000631 (96/152198) while in subpopulation AFR AF = 0.00219 (91/41530). AF 95% confidence interval is 0.00183. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 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.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.778A>T	p.Thr260Ser	missense_variant	Exon 7 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.778A>T	p.Thr260Ser	missense_variant	Exon 7 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.817A>T	p.Thr273Ser	missense_variant	Exon 7 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*264A>T		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.817A>T		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*264A>T		3_prime_UTR_variant	Exon 6 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000957

GnomAD2 exomes

AF:

0.000193

AC:

AN:

232982

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.0000911

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000956

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000704

AC:

102

AN:

1447846

Hom.:

Cov.:

AF XY:

0.0000487

AC XY:

AN XY:

718416

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33068

American (AMR)

AF:

0.000231

AC:

AN:

43312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25686

East Asian (EAS)

AF:

0.00

AC:

AN:

39282

South Asian (SAS)

AF:

0.00

AC:

AN:

84378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105086

Other (OTH)

AF:

0.000201

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000631

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41530

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000201

Hom.:

Bravo

AF:

0.000688

ESP6500AA

AF:

0.00166

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1H-related disorder

Benign:1

Jun 16, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Jul 30, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.36

T;.;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.51

T;T;T;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.11

N;.;N;N

PhyloP100

4.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.14

N;.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.93

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

0.019

B;.;B;B

Vest4

0.18

MutPred

0.48

Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);

MVP

0.69

ClinPred

0.015

GERP RS

4.4

Varity_R

0.070

gMVP

0.75

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over