rs58615599

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021098.3(CACNA1H):c.2881C>A(p.Leu961Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L961L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91

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:

ENSG00000261294 (HGNC:):

ENSG00000261294 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 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.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.2842C>A	p.Leu948Met	missense_variant	Exon 13 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.2842C>A	p.Leu948Met	missense_variant	Exon 13 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2881C>A	p.Leu961Met	missense_variant	Exon 13 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*794C>A		non_coding_transcript_exon_variant	Exon 13 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2328C>A		non_coding_transcript_exon_variant	Exon 12 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2881C>A		non_coding_transcript_exon_variant	Exon 13 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*794C>A		3_prime_UTR_variant	Exon 13 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2328C>A		3_prime_UTR_variant	Exon 12 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1446596

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718020

African (AFR)

AF:

0.00

AC:

AN:

33236

American (AMR)

AF:

0.00

AC:

AN:

42836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39038

South Asian (SAS)

AF:

0.00

AC:

AN:

83766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104578

Other (OTH)

AF:

0.00

AC:

AN:

59818

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2881C>A (p.L961M) alteration is located in exon 13 (coding exon 12) of the CACNA1H gene. This alteration results from a C to A substitution at nucleotide position 2881, causing the leucine (L) at amino acid position 961 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;.;L;L

PhyloP100

4.9

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.024

D;.;D;D

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.59

MutPred

0.68

Loss of stability (P = 0.2774);.;Loss of stability (P = 0.2774);Loss of stability (P = 0.2774);

MVP

0.90

ClinPred

0.96

GERP RS

1.3

Varity_R

0.66

gMVP

0.61

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over