rs554182970

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.4269G>C(p.Leu1423Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,038 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000055 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.189

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 16-1211213-G-C is Benign according to our data. Variant chr16-1211213-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 460112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.189 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000263 (4/152344) while in subpopulation SAS AF = 0.000828 (4/4832). AF 95% confidence interval is 0.000282. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 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.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4230G>C	p.Leu1410Leu	synonymous_variant	Exon 22 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4230G>C	p.Leu1410Leu	synonymous_variant	Exon 22 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4269G>C	p.Leu1423Leu	synonymous_variant	Exon 22 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*239G>C		non_coding_transcript_exon_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2182G>C		non_coding_transcript_exon_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3716G>C		non_coding_transcript_exon_variant	Exon 21 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4269G>C		non_coding_transcript_exon_variant	Exon 22 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*239G>C		3_prime_UTR_variant	Exon 22 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2182G>C		3_prime_UTR_variant	Exon 22 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3716G>C		3_prime_UTR_variant	Exon 21 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000966

AC:

AN:

248538

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000166

GnomAD4 exome

AF:

0.0000548

AC:

AN:

1460694

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

726620

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000823

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111718

Other (OTH)

AF:

0.0000828

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000263

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 23, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.41

(source)

DANN

Benign

0.46

PhyloP100

-0.19

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over