rs57181695

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021098.3(CACNA1H):c.5253C>A(p.Asn1751Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1751N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.49

Publications

3 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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 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.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5268C>A	p.Asn1756Lys	missense_variant	Exon 30 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5271C>A	p.Asn1757Lys	missense_variant	Exon 30 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5235C>A	p.Asn1745Lys	missense_variant	Exon 30 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5268C>A	p.Asn1756Lys	missense_variant	Exon 31 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5214C>A	p.Asn1738Lys	missense_variant	Exon 31 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5235C>A	p.Asn1745Lys	missense_variant	Exon 30 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5196C>A	p.Asn1732Lys	missense_variant	Exon 30 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5235C>A	p.Asn1745Lys	missense_variant	Exon 30 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5253C>A	p.Asn1751Lys	missense_variant	Exon 31 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5253C>A		non_coding_transcript_exon_variant	Exon 31 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1205C>A		non_coding_transcript_exon_variant	Exon 30 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*334C>A		non_coding_transcript_exon_variant	Exon 31 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3104C>A		non_coding_transcript_exon_variant	Exon 31 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4697C>A		non_coding_transcript_exon_variant	Exon 29 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*112C>A		non_coding_transcript_exon_variant	Exon 31 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*112C>A		non_coding_transcript_exon_variant	Exon 31 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*254C>A		non_coding_transcript_exon_variant	Exon 31 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5253C>A		non_coding_transcript_exon_variant	Exon 31 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5253C>A		non_coding_transcript_exon_variant	Exon 31 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5235C>A		non_coding_transcript_exon_variant	Exon 30 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5253C>A		non_coding_transcript_exon_variant	Exon 31 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5253C>A		non_coding_transcript_exon_variant	Exon 31 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*254C>A		non_coding_transcript_exon_variant	Exon 30 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1205C>A		3_prime_UTR_variant	Exon 30 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*334C>A		3_prime_UTR_variant	Exon 31 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3104C>A		3_prime_UTR_variant	Exon 31 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4697C>A		3_prime_UTR_variant	Exon 29 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*112C>A		3_prime_UTR_variant	Exon 31 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*112C>A		3_prime_UTR_variant	Exon 31 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*254C>A		3_prime_UTR_variant	Exon 31 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*254C>A		3_prime_UTR_variant	Exon 30 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450442

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720428

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

42964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.00

AC:

AN:

84038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106760

Other (OTH)

AF:

0.00

AC:

AN:

59966

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D;D;.

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.

PhyloP100

2.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.9

D;.;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.85

MutPred

0.85

Gain of ubiquitination at N1751 (P = 0.0388);.;.;.;

MVP

0.98

ClinPred

1.0

GERP RS

3.6

Varity_R

0.98

gMVP

0.90

Mutation Taster

=64/36

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over