rs746967306

Positions:

chr16-1218616-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_021098.3(CACNA1H):c.5852T>A(p.Val1951Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,555,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000068 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.583

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12965441).

BP6

Variant 16-1218616-T-A is Benign according to our data. Variant chr16-1218616-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 578030.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.5852T>A	p.Val1951Glu	missense_variant	33/35	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.5852T>A	p.Val1951Glu	missense_variant	33/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.5834T>A	p.Val1945Glu	missense_variant	31/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.5813T>A	p.Val1938Glu	missense_variant	33/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 linkuse as main transcript	c.2090T>A	p.Val697Glu	missense_variant	15/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 linkuse as main transcript	c.2075T>A	p.Val692Glu	missense_variant	16/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 linkuse as main transcript	c.2057T>A	p.Val686Glu	missense_variant	15/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*933T>A		non_coding_transcript_exon_variant	33/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*3703T>A		non_coding_transcript_exon_variant	33/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*933T>A		3_prime_UTR_variant	33/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*3703T>A		3_prime_UTR_variant	33/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000680

AC:

AN:

147006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

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:

0.0000897

Gnomad OTH

AF:

0.000496

GnomAD3 exomes

AF:

0.0000999

AC:

AN:

170152

Hom.:

AF XY:

0.0000984

AC XY:

AN XY:

91450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000766

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000375

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

AF:

0.0000681

AC:

AN:

1408846

Hom.:

Cov.:

AF XY:

0.0000690

AC XY:

AN XY:

695788

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000329

Gnomad4 NFE exome

AF:

0.0000636

Gnomad4 OTH exome

AF:

0.000137

GnomAD4 genome

AF:

0.0000680

AC:

AN:

147100

Hom.:

Cov.:

AF XY:

0.0000699

AC XY:

AN XY:

71524

show subpopulations

Gnomad4 AFR

AF:

0.0000254

Gnomad4 AMR

AF:

0.000135

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000897

Gnomad4 OTH

AF:

0.000491

Alfa

AF:

0.0000822

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000342

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

0.0065

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.65

T;T;T;.

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Uncertain

0.056

MutationAssessor

Uncertain

2.1

M;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

N;.;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.63

T;.;T;T

Sift4G

Benign

0.84

T;.;T;T

Polyphen

0.93

P;.;P;P

Vest4

0.60

MVP

0.93

ClinPred

0.13

GERP RS

2.3

Varity_R

0.38

gMVP

0.44

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

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