16-1220176-C-T

Position:

chr16-1220176-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.6244C>T(p.Arg2082Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,520,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.00800

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12935069).

BP6

Variant 16-1220176-C-T is Benign according to our data. Variant chr16-1220176-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.6244C>T	p.Arg2082Trp	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.6244C>T	p.Arg2082Trp	missense_variant	35/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.6226C>T	p.Arg2076Trp	missense_variant	33/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.6205C>T	p.Arg2069Trp	missense_variant	35/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 linkuse as main transcript	c.2482C>T	p.Arg828Trp	missense_variant	17/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 linkuse as main transcript	c.2434C>T	p.Arg812Trp	missense_variant	18/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 linkuse as main transcript	c.2416C>T	p.Arg806Trp	missense_variant	17/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*1292C>T		non_coding_transcript_exon_variant	35/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*4062C>T		non_coding_transcript_exon_variant	35/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.*1292C>T		3_prime_UTR_variant	35/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*4062C>T		3_prime_UTR_variant	35/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000509

AC:

AN:

157236

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

87810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000953

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000603

Gnomad FIN exome

AF:

0.000197

Gnomad NFE exome

AF:

0.0000261

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1368002

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

673956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000126

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000105

Gnomad4 NFE exome

AF:

0.0000392

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74340

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:

0.0000941

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000846

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.6244C>T (p.R2082W) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 6244, causing the arginine (R) at amino acid position 2082 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

CACNA1H: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.80

T;T;T;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;.;D;D

REVEL

Benign

0.099

Sift

Uncertain

0.0050

D;.;D;D

Sift4G

Uncertain

0.018

D;.;D;D

Polyphen

0.0030

B;.;D;D

Vest4

0.19

MutPred

0.22

Loss of glycosylation at S2081 (P = 0.0321);.;.;.;

MVP

0.43

ClinPred

0.29

GERP RS

1.3

Varity_R

0.25

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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