NM_021098.3:c.5052G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_021098.3(CACNA1H):c.5052G>A(p.Leu1684Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,604,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.06

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 16-1215254-G-A is Benign according to our data. Variant chr16-1215254-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 529624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.06 with no splicing effect.

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 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.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5067G>A	p.Leu1689Leu	synonymous_variant	Exon 28 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5070G>A	p.Leu1690Leu	synonymous_variant	Exon 28 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5034G>A	p.Leu1678Leu	synonymous_variant	Exon 28 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5067G>A	p.Leu1689Leu	synonymous_variant	Exon 29 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5013G>A	p.Leu1671Leu	synonymous_variant	Exon 29 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5034G>A	p.Leu1678Leu	synonymous_variant	Exon 28 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4995G>A	p.Leu1665Leu	synonymous_variant	Exon 28 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5034G>A	p.Leu1678Leu	synonymous_variant	Exon 28 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5052G>A	p.Leu1684Leu	synonymous_variant	Exon 29 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5052G>A		non_coding_transcript_exon_variant	Exon 29 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1004G>A		non_coding_transcript_exon_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*133G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2903G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4496G>A		non_coding_transcript_exon_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5034G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5034G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*53G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5052G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5052G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5034G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5052G>A		non_coding_transcript_exon_variant	Exon 29 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5052G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*53G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1004G>A		3_prime_UTR_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*133G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2903G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4496G>A		3_prime_UTR_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*53G>A		3_prime_UTR_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*53G>A		3_prime_UTR_variant	Exon 28 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000425

AC:

AN:

235424

AF XY:

0.00000780

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:

0.00000942

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000289

AC:

AN:

1452322

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

721482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.00

AC:

AN:

43772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

39428

South Asian (SAS)

AF:

0.00

AC:

AN:

84698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000361

AC:

AN:

1107620

Other (OTH)

AF:

0.0000333

AC:

AN:

60034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000329

Hom.:

Bravo

AF:

0.00000756

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 29, 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

Apr 30, 2021

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

-0.50

CADD

Benign

6.4

(source)

DANN

Benign

0.81

PhyloP100

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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