rs774660673

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

The NM_021098.3(CACNA1H):c.6311_6325delTCACCAGCTCCGCCT(p.Ile2104_Cys2109delinsSer) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000379 in 1,584,744 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I2104I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000017 ( 0 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: 4.81

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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_021098.3.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000237 (36/152086) while in subpopulation AMR AF = 0.00216 (33/15284). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 36 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6311_6325delTCACCAGCTCCGCCT	p.Ile2104_Cys2109delinsSer	disruptive_inframe_deletion	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6293_6307delTCACCAGCTCCGCCT	p.Ile2098_Cys2103delinsSer	disruptive_inframe_deletion	Exon 34 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6311_6325delTCACCAGCTCCGCCT	p.Ile2104_Cys2109delinsSer	disruptive_inframe_deletion	Exon 35 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.6326_6340delTCACCAGCTCCGCCT	p.Ile2109_Cys2114delinsSer	disruptive_inframe_deletion	Exon 34 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.6296_6310delTCACCAGCTCCGCCT	p.Ile2099_Cys2104delinsSer	disruptive_inframe_deletion	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.0000333

AC:

AN:

210298

AF XY:

0.0000254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1432658

Hom.:

AF XY:

0.0000140

AC XY:

AN XY:

712442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31278

American (AMR)

AF:

0.000279

AC:

AN:

43050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25352

East Asian (EAS)

AF:

0.00

AC:

AN:

37914

South Asian (SAS)

AF:

0.00

AC:

AN:

84224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000453

AC:

AN:

1103734

Other (OTH)

AF:

0.000118

AC:

AN:

59422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.000237

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00216

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00143

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000434

Hom.:

Bravo

AF:

0.000204

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=77/123

disease causing (long InDel)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over