16-1219003-A-G

Position:

chr16-1219003-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_021098.3(CACNA1H):c.5921A>G(p.Glu1974Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,550,202 control chromosomes in the GnomAD database, including 1,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 408 hom., cov: 31)

Exomes 𝑓: 0.025 ( 784 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.692

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 -16 ACMG points.

BP6

Variant 16-1219003-A-G is Benign according to our data. Variant chr16-1219003-A-G is described in ClinVar as [Benign]. Clinvar id is 446956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.5921A>G	p.Glu1974Gly	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 linkuse as main transcript	c.5921A>G	p.Glu1974Gly	missense_variant	34/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.5903A>G	p.Glu1968Gly	missense_variant	32/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.5882A>G	p.Glu1961Gly	missense_variant	34/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 linkuse as main transcript	c.2159A>G	p.Glu720Gly	missense_variant	16/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 linkuse as main transcript	c.2111A>G	p.Glu704Gly	missense_variant, splice_region_variant	17/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 linkuse as main transcript	c.2093A>G	p.Glu698Gly	missense_variant, splice_region_variant	16/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*969A>G		splice_region_variant, non_coding_transcript_exon_variant	34/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*3739A>G		splice_region_variant, non_coding_transcript_exon_variant	34/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*969A>G		3_prime_UTR_variant	34/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*3739A>G		3_prime_UTR_variant	34/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0515

AC:

7832

AN:

152066

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0349

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.0964

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.00790

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0435

GnomAD3 exomes

AF:

0.0345

AC:

5338

AN:

154678

Hom.:

167

AF XY:

0.0332

AC XY:

2731

AN XY:

82252

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.0454

Gnomad ASJ exome

AF:

0.00684

Gnomad EAS exome

AF:

0.0858

Gnomad SAS exome

AF:

0.0394

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0252

AC:

35188

AN:

1398018

Hom.:

784

Cov.:

AF XY:

0.0250

AC XY:

17270

AN XY:

689532

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0444

Gnomad4 ASJ exome

AF:

0.00648

Gnomad4 EAS exome

AF:

0.0803

Gnomad4 SAS exome

AF:

0.0377

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0517

AC:

7866

AN:

152184

Hom.:

408

Cov.:

AF XY:

0.0508

AC XY:

3783

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.0349

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.0968

Gnomad4 SAS

AF:

0.0420

Gnomad4 FIN

AF:

0.00790

Gnomad4 NFE

AF:

0.0181

Gnomad4 OTH

AF:

0.0426

Alfa

AF:

0.0218

Hom.:

110

Bravo

AF:

0.0567

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.0999

AC:

341

ESP6500EA

AF:

0.0150

AC:

102

ExAC

AF:

0.0216

AC:

919

Asia WGS

AF:

0.0780

AC:

269

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 26, 2017

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.46

T;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.65

T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-0.77

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;.;D;D

REVEL

Benign

0.18

Sift

Benign

0.050

D;.;D;D

Sift4G

Benign

0.23

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.17

ClinPred

0.010

GERP RS

2.1

Varity_R

0.096

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 0

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