16-1202204-C-T

Position:

chr16-1202204-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.1754C>T(p.Pro585Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,553,320 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 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.62

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043373913).

BP6

Variant 16-1202204-C-T is Benign according to our data. Variant chr16-1202204-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529630.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (34/152364) while in subpopulation AFR AF= 0.000793 (33/41594). AF 95% confidence interval is 0.00058. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.1754C>T	p.Pro585Leu	missense_variant	9/35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.1754C>T	p.Pro585Leu	missense_variant	9/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.1754C>T	p.Pro585Leu	missense_variant	8/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.1715C>T	p.Pro572Leu	missense_variant	9/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000639478.1 link	n.1754C>T		non_coding_transcript_exon_variant	9/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.1385+369C>T		intron_variant		5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000936

AC:

AN:

149586

Hom.:

AF XY:

0.0000494

AC XY:

AN XY:

81000

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000378

AC:

AN:

1400956

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

691564

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000629

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000647

Gnomad4 OTH exome

AF:

0.0000688

GnomAD4 genome

AF:

0.000223

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000793

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.000602

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000280

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign: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

Jun 06, 2023

The c.1754C>T (p.P585L) alteration is located in exon 9 (coding exon 8) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 1754, causing the proline (P) at amino acid position 585 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2023

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

0.083

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;T;.

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.1

M;.;M;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

D;.;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.26

T;.;T;T

Sift4G

Benign

0.12

T;.;T;T

Polyphen

0.16

B;.;D;D

Vest4

0.49

MVP

0.97

ClinPred

0.13

GERP RS

4.4

Varity_R

0.18

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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