rs371500703

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.3101C>T(p.Thr1034Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,603,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1034T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.412

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23802483).

BP6

Variant 16-1207807-C-T is Benign according to our data. Variant chr16-1207807-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460077.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 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.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3062C>T	p.Thr1021Met	missense_variant	Exon 15 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3062C>T	p.Thr1021Met	missense_variant	Exon 15 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3101C>T	p.Thr1034Met	missense_variant	Exon 15 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1014C>T		non_coding_transcript_exon_variant	Exon 15 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2548C>T		non_coding_transcript_exon_variant	Exon 14 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3101C>T		non_coding_transcript_exon_variant	Exon 15 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1014C>T		3_prime_UTR_variant	Exon 15 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2548C>T		3_prime_UTR_variant	Exon 14 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000304

AC:

AN:

230230

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.0000723

Gnomad AMR exome

AF:

0.0000305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000599

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000387

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000427

AC:

AN:

1450982

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

720854

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33260

American (AMR)

AF:

0.0000231

AC:

AN:

43346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39070

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000506

AC:

AN:

1107170

Other (OTH)

AF:

0.0000333

AC:

AN:

59988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000394

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.0000282

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Mar 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3101C>T (p.T1034M) alteration is located in exon 15 (coding exon 14) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 3101, causing the threonine (T) at amino acid position 1034 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;.

Eigen

Benign

0.033

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.33

T;T;T;.

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.5

M;.;M;M

PhyloP100

0.41

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.23

T;.;T;T

Sift4G

Benign

0.11

T;.;T;T

Polyphen

1.0

D;.;D;D

Vest4

0.38

MVP

0.84

ClinPred

0.43

GERP RS

3.6

Varity_R

0.038

gMVP

0.36

Mutation Taster

=89/11

polymorphism

(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