rs201855332

Positions:

chr16-1210868-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_021098.3(CACNA1H):c.4120G>A(p.Val1374Met) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,605,478 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.60

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 Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000354 (515/1453218) while in subpopulation AMR AF= 0.000559 (25/44716). AF 95% confidence interval is 0.000395. There are 2 homozygotes in gnomad4_exome. There are 227 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.4120G>A	p.Val1374Met	missense_variant	21/35	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.4120G>A	p.Val1374Met	missense_variant	21/35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 linkuse as main transcript	c.4120G>A	p.Val1374Met	missense_variant	20/33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 linkuse as main transcript	c.4081G>A	p.Val1361Met	missense_variant	21/35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	4/17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	4/18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	4/17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000637236.2 linkuse as main transcript	n.*90G>A		non_coding_transcript_exon_variant	5/6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 linkuse as main transcript	n.4120G>A		non_coding_transcript_exon_variant	21/35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*2033G>A		non_coding_transcript_exon_variant	21/35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000637236.2 linkuse as main transcript	n.*90G>A		3_prime_UTR_variant	5/6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 linkuse as main transcript	n.*2033G>A		3_prime_UTR_variant	21/35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

243392

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

132852

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000357

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000354

AC:

515

AN:

1453218

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

227

AN XY:

723292

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000177

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2023	Variant summary: CACNA1H c.4120G>A (p.Val1374Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 243392 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4120G>A in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2017	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1374 of the CACNA1H protein (p.Val1374Met). This variant is present in population databases (rs201855332, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 446952). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1H protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;.;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

N;.;N;N

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.0030

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.71

MVP

0.94

ClinPred

0.22

GERP RS

4.2

Varity_R

0.66

gMVP

0.82

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