rs746597383

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM4PP3BS2

The NM_021098.3(CACNA1H):c.3422_3442delGGCGCTCCAGCTGGAGCAGCC(p.Arg1141_Ser1147del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000815 in 1,545,100 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.53

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 -1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021098.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 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.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3383_3403delGGCGCTCCAGCTGGAGCAGCC	p.Arg1128_Ser1134del	disruptive_inframe_deletion	Exon 17 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3383_3403delGGCGCTCCAGCTGGAGCAGCC	p.Arg1128_Ser1134del	disruptive_inframe_deletion	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3422_3442delGGCGCTCCAGCTGGAGCAGCC	p.Arg1141_Ser1147del	disruptive_inframe_deletion	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1335_1355delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.2869_2889delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3422_3442delGGCGCTCCAGCTGGAGCAGCC		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.1335_1355delGGCGCTCCAGCTGGAGCAGCC		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.2869_2889delGGCGCTCCAGCTGGAGCAGCC		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000950

AC:

AN:

147410

AF XY:

0.0000976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000456

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000762

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000768

AC:

107

AN:

1392916

Hom.:

AF XY:

0.0000727

AC XY:

AN XY:

687594

show subpopulations

African (AFR)

AF:

0.000322

AC:

AN:

31062

American (AMR)

AF:

0.000268

AC:

AN:

33528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24290

East Asian (EAS)

AF:

0.0000274

AC:

AN:

36534

South Asian (SAS)

AF:

0.000129

AC:

AN:

77544

European-Finnish (FIN)

AF:

0.0000443

AC:

AN:

45158

Middle Eastern (MID)

AF:

0.000365

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

0.0000610

AC:

AN:

1081656

Other (OTH)

AF:

0.000121

AC:

AN:

57668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.000125

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41448

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.0000435

Hom.:

Bravo

AF:

0.000113

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Mar 07, 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

Uncertain:1

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.3422_3442del, results in the deletion of 7 amino acid(s) of the CACNA1H protein (p.Arg1141_Ser1147del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs754765356, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 460087). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.5

Mutation Taster

=193/7

polymorphism

(source)

Splicing

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