16-1210047-C-T

Position:

chr16-1210047-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_021098.3(CACNA1H):c.3757C>T(p.Arg1253Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,550,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.24

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 -9 ACMG points.

BP6

Variant 16-1210047-C-T is Benign according to our data. Variant chr16-1210047-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572338.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000162 (226/1398740) while in subpopulation MID AF= 0.000887 (5/5636). AF 95% confidence interval is 0.00035. There are 0 homozygotes in gnomad4_exome. There are 110 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3757C>T	p.Arg1253Cys	missense_variant	18/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.3757C>T	p.Arg1253Cys	missense_variant	18/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.3757C>T	p.Arg1253Cys	missense_variant	17/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.3718C>T	p.Arg1240Cys	missense_variant	18/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000637236.2 link	n.120C>T		non_coding_transcript_exon_variant	2/6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3757C>T		non_coding_transcript_exon_variant	18/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1670C>T		non_coding_transcript_exon_variant	18/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000640028.1 link	n.*1670C>T		3_prime_UTR_variant	18/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000569107.5 link	c.-21C>T		upstream_gene_variant		1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.-21C>T		upstream_gene_variant		1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.-21C>T		upstream_gene_variant		1		ENSP00000454581.2	H3BMW6

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152200

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

153628

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

81902

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.0000401

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000438

Gnomad FIN exome

AF:

0.0000670

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000462

GnomAD4 exome

AF:

0.000162

AC:

226

AN:

1398740

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

110

AN XY:

690100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000632

Gnomad4 AMR exome

AF:

0.000139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.0000421

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

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:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000246

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000863

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2024

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.3757C>T (p.R1253C) alteration is located in exon 18 (coding exon 17) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 3757, causing the arginine (R) at amino acid position 1253 to be replaced by a cysteine (C). 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, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;.;.

Eigen

Benign

0.024

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.93

D;D;D;.

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

H;.;H;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.7

D;.;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.010

D;.;D;D

Sift4G

Uncertain

0.0040

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.78

MVP

0.98

ClinPred

0.78

GERP RS

1.7

Varity_R

0.29

gMVP

0.78

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