rs761945003

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_021098.3(CACNA1H):c.4814C>A(p.Pro1605His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,582,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1605L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.03

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16984102).

BP6

Variant 16-1213816-C-A is Benign according to our data. Variant chr16-1213816-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1000691.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 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.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4829C>A	p.Pro1610His	missense_variant	Exon 26 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4832C>A	p.Pro1611His	missense_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4796C>A	p.Pro1599His	missense_variant	Exon 26 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4829C>A	p.Pro1610His	missense_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4775C>A	p.Pro1592His	missense_variant	Exon 27 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4796C>A	p.Pro1599His	missense_variant	Exon 26 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4757C>A	p.Pro1586His	missense_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4796C>A	p.Pro1599His	missense_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4814C>A	p.Pro1605His	missense_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4814C>A		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*766C>A		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4752C>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2665C>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4258C>A		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4796C>A		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4796C>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4891C>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4814C>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4814C>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4796C>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4814C>A		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4814C>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4873C>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*766C>A		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2665C>A		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4258C>A		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000101

AC:

AN:

198706

AF XY:

0.0000186

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000489

AC:

AN:

1430330

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

708828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32936

American (AMR)

AF:

0.00

AC:

AN:

39378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25606

East Asian (EAS)

AF:

0.00

AC:

AN:

38292

South Asian (SAS)

AF:

0.00

AC:

AN:

82134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000638

AC:

AN:

1097970

Other (OTH)

AF:

0.00

AC:

AN:

59358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Aug 31, 2022

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

0.11

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.29

T;.;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

T;T;T;.

M_CAP

Benign

0.054

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Uncertain

0.43

PhyloP100

3.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

D;.;D;D

REVEL

Benign

0.25

Sift

Benign

0.62

T;.;T;T

Sift4G

Benign

0.25

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.44

MutPred

0.29

Loss of glycosylation at P1605 (P = 0.0394);.;.;.;

MVP

0.79

ClinPred

0.30

GERP RS

2.8

Varity_R

0.19

gMVP

0.67

Mutation Taster

=78/22

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over