16-1209405-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.3737C>T(p.Ser1246Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000764 in 1,597,532 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. S1246P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.66

Publications

2 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05472985).

BP6

Variant 16-1209405-C-T is Benign according to our data. Variant chr16-1209405-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 567929.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000768 (111/1445198) while in subpopulation MID AF = 0.000868 (5/5762). AF 95% confidence interval is 0.000341. There are 1 homozygotes in GnomAdExome4. There are 53 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3737C>T	p.Ser1246Leu	missense_variant	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.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 17 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.3698C>T	p.Ser1233Leu	missense_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.3737C>T	p.Ser1246Leu	missense_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1650C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3184C>T		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.3737C>T		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*1650C>T		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3184C>T		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000868

AC:

AN:

230302

AF XY:

0.0000785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.000512

Gnomad EAS exome

AF:

0.0000570

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000935

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000768

AC:

111

AN:

1445198

Hom.:

Cov.:

AF XY:

0.0000737

AC XY:

AN XY:

719304

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33386

American (AMR)

AF:

0.0000448

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26078

East Asian (EAS)

AF:

0.000126

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37890

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

1111328

Other (OTH)

AF:

0.0000997

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000722

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000171

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000842

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jun 02, 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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.073

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.084

T;T;T;.

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.055

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

-1.1

N;.;N;N

PhyloP100

2.7

PrimateAI

Benign

0.32

PROVEAN

Benign

0.27

N;.;N;N

REVEL

Benign

0.28

Sift

Benign

0.67

T;.;T;T

Sift4G

Benign

0.32

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.093

MutPred

0.37

Gain of helix (P = 0.0117);.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);

MVP

0.29

ClinPred

0.017

GERP RS

2.9

Varity_R

0.025

gMVP

0.34

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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