chr16-1208121-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_021098.3(CACNA1H):c.3263C>T(p.Pro1088Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,593,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1088S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.30

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 -5 ACMG points.

BP6

Variant 16-1208121-C-T is Benign according to our data. Variant chr16-1208121-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 583058.

BS2

High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 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.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3224C>T	p.Pro1075Leu	missense_variant	Exon 16 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3224C>T	p.Pro1075Leu	missense_variant	Exon 16 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3263C>T	p.Pro1088Leu	missense_variant	Exon 16 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1176C>T		non_coding_transcript_exon_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2710C>T		non_coding_transcript_exon_variant	Exon 15 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3263C>T		non_coding_transcript_exon_variant	Exon 16 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1176C>T		3_prime_UTR_variant	Exon 16 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*2710C>T		3_prime_UTR_variant	Exon 15 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000231

AC:

AN:

216526

AF XY:

0.00000850

show subpopulations

Gnomad AFR exome

AF:

0.000326

Gnomad AMR exome

AF:

0.0000314

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:

0.00

GnomAD4 exome

AF:

0.0000368

AC:

AN:

1441804

Hom.:

Cov.:

AF XY:

0.0000447

AC XY:

AN XY:

715484

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

32888

American (AMR)

AF:

0.0000235

AC:

AN:

42548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25746

East Asian (EAS)

AF:

0.00

AC:

AN:

38324

South Asian (SAS)

AF:

0.00

AC:

AN:

82696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5330

European-Non Finnish (NFE)

AF:

0.0000426

AC:

AN:

1103740

Other (OTH)

AF:

0.00

AC:

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

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:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000494

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000333

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3263C>T (p.P1088L) alteration is located in exon 16 (coding exon 15) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 3263, causing the proline (P) at amino acid position 1088 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;.

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.74

D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.5

M;.;M;M

PhyloP100

7.3

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.1

D;.;D;D

REVEL

Uncertain

0.51

Sift

Benign

0.069

T;.;T;T

Sift4G

Benign

0.12

T;.;T;T

Polyphen

1.0

D;.;D;D

Vest4

0.63

MVP

0.91

ClinPred

0.63

GERP RS

4.0

Varity_R

0.34

gMVP

0.52

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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