rs767196759

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_021098.3(CACNA1H):c.1937A>C(p.His646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H646Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.596

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.106597364).

BP6

Variant 16-1202387-A-C is Benign according to our data. Variant chr16-1202387-A-C is described in ClinVar as Benign. ClinVar VariationId is 529554.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 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.1937A>C	p.His646Pro	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.1898A>C	p.His633Pro	missense_variant	Exon 9 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.1898A>C	p.His633Pro	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.1937A>C	p.His646Pro	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000711442.1 link	n.*1384A>C		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.1937A>C		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*1384A>C		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1 link	n.1385+552A>C		intron_variant	Intron 9 of 34	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000680

AC:

AN:

146980

AF XY:

0.0000126

show subpopulations

Gnomad AFR exome

AF:

0.000139

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396236

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688692

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31738

American (AMR)

AF:

0.00

AC:

AN:

35858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24850

East Asian (EAS)

AF:

0.00

AC:

AN:

35956

South Asian (SAS)

AF:

0.00

AC:

AN:

78552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079528

Other (OTH)

AF:

0.00

AC:

AN:

57970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ExAC

AF:

0.00000924

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Aug 09, 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

0.069

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.14

T;.;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.46

T;T;T;.

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

0.072

MutationAssessor

Uncertain

2.5

M;.;M;M

PhyloP100

0.60

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Benign

0.25

Sift

Benign

0.31

T;.;T;T

Sift4G

Benign

0.26

T;.;T;T

Polyphen

0.17

B;.;B;B

Vest4

0.30

MutPred

0.36

Gain of relative solvent accessibility (P = 0.0104);.;Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);

MVP

0.81

ClinPred

0.13

GERP RS

2.9

Varity_R

0.21

gMVP

0.30

Mutation Taster

=82/18

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over