rs775271588

Positions:

chr16-1220830-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP5_ModerateBP4BS2

The NM_021098.3(CACNA1H):c.6898A>G(p.Ile2300Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.778

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:

CACNA1H (HGNC:):

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant 16-1220830-A-G is Pathogenic according to our data. Variant chr16-1220830-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402205.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-1220830-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.054704905). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.6898A>G	p.Ile2300Val	missense_variant	35/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.6898A>G	p.Ile2300Val	missense_variant	35/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.6880A>G	p.Ile2294Val	missense_variant	33/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.6859A>G	p.Ile2287Val	missense_variant	35/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 linkuse as main transcript	c.3136A>G	p.Ile1046Val	missense_variant	17/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 linkuse as main transcript	c.3088A>G	p.Ile1030Val	missense_variant	18/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 linkuse as main transcript	c.3070A>G	p.Ile1024Val	missense_variant	17/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*1946A>G		non_coding_transcript_exon_variant	35/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*4716A>G		non_coding_transcript_exon_variant	35/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*1946A>G		3_prime_UTR_variant	35/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*4716A>G		3_prime_UTR_variant	35/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152046

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000644

AC:

AN:

248326

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.0000713

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460546

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000306

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000828

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Abnormal brain morphology

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.098

DANN

Benign

0.41

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.44

T;T;T;.

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.055

T;T;T;T

MetaSVM

Uncertain

-0.046

MutationAssessor

Benign

0.34

N;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

0.030

N;.;N;N

REVEL

Benign

0.20

Sift

Benign

0.46

T;.;T;T

Sift4G

Benign

0.54

T;.;T;T

Polyphen

0.0040

B;.;B;B

Vest4

0.051

MutPred

0.14

Gain of sheet (P = 0.0125);.;.;.;

MVP

0.72

ClinPred

0.53

GERP RS

0.24

Varity_R

0.048

gMVP

0.056

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over