rs558813483

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_021098.3(CACNA1H):c.5974G>A(p.Gly1992Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,549,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.224

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040793985).

BP6

Variant 16-1219056-G-A is Benign according to our data. Variant chr16-1219056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5974G>A	p.Gly1992Ser	missense_variant	34/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.5974G>A	p.Gly1992Ser	missense_variant	34/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.5956G>A	p.Gly1986Ser	missense_variant	32/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.5935G>A	p.Gly1979Ser	missense_variant	34/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.2212G>A	p.Gly738Ser	missense_variant	16/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.2164G>A	p.Gly722Ser	missense_variant	17/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.2146G>A	p.Gly716Ser	missense_variant	16/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 link	n.*1022G>A		non_coding_transcript_exon_variant	34/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3792G>A		non_coding_transcript_exon_variant	34/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 link	n.*1022G>A		3_prime_UTR_variant	34/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3792G>A		3_prime_UTR_variant	34/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000592

AC:

AN:

152012

Hom.:

AF XY:

0.0000246

AC XY:

AN XY:

81212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000244

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000172

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1397620

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

689362

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000280

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000649

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.20

CADD

Benign

1.8

DANN

Benign

0.69

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.43

T;T;T;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Uncertain

-0.099

MutationAssessor

Benign

-1.2

N;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.10

N;.;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.49

T;.;T;T

Sift4G

Benign

0.66

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.015

MutPred

0.22

Gain of phosphorylation at G1992 (P = 0.0057);.;.;.;

MVP

0.76

ClinPred

0.028

GERP RS

-0.12

Varity_R

0.071

gMVP

0.22

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