16-1153750-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,212,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A5S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.369

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099538594).

BP6

Variant 16-1153750-G-A is Benign according to our data. Variant chr16-1153750-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 800247.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000536 (81/151074) while in subpopulation AFR AF = 0.00184 (76/41342). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 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.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.13G>A	p.Ala5Thr	missense_variant	Exon 2 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.13G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.000537

AC:

AN:

150972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.0000148

Gnomad OTH

AF:

0.000965

GnomAD2 exomes

AF:

0.00

AC:

AN:

454

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ 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:

0.0000500

AC:

AN:

1060948

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

501894

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

21700

American (AMR)

AF:

0.00

AC:

AN:

7370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12860

East Asian (EAS)

AF:

0.00

AC:

AN:

23512

South Asian (SAS)

AF:

0.00

AC:

AN:

22412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2764

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

907674

Other (OTH)

AF:

0.0000480

AC:

AN:

41646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000536

AC:

AN:

151074

Hom.:

Cov.:

AF XY:

0.000569

AC XY:

AN XY:

73840

show subpopulations

African (AFR)

AF:

0.00184

AC:

AN:

41342

American (AMR)

AF:

0.000132

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67646

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000438

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 10, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.13G>A (p.A5T) alteration is located in exon 2 (coding exon 1) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Oct 08, 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

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

9.3

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.097

T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.46

T;T;T;.

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.0

N;.;N;N

PhyloP100

-0.37

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.10

N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.73

T;.;T;T

Sift4G

Benign

0.62

T;.;T;T

Polyphen

0.0040

B;.;B;B

Vest4

0.033

MutPred

0.12

Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);

MVP

0.34

ClinPred

0.017

GERP RS

0.79

PromoterAI

0.018

Neutral

(source)

Varity_R

0.038

gMVP

0.27

Mutation Taster

=89/11

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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16-1153750-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over