chr16-1220557-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.6625G>C(p.Ala2209Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,531,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.249

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.093827456).

BP6

Variant 16-1220557-G-C is Benign according to our data. Variant chr16-1220557-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460172.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152048) while in subpopulation NFE AF = 0.000427 (29/67936). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6625G>C	p.Ala2209Pro	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6607G>C	p.Ala2203Pro	missense	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6625G>C	p.Ala2209Pro	missense	Exon 35 of 35	ENSP00000334198.7
CACNA1H	ENST00000569107.6	TSL:1	c.6640G>C	p.Ala2214Pro	missense	Exon 34 of 34	ENSP00000454990.2
CACNA1H	ENST00000711493.1		c.6610G>C	p.Ala2204Pro	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000427

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000238

AC:

AN:

167994

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.0000957

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000425

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000319

AC:

440

AN:

1379032

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

211

AN XY:

679326

show subpopulations

African (AFR)

AF:

0.0000659

AC:

AN:

30356

American (AMR)

AF:

0.000102

AC:

AN:

29526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20428

East Asian (EAS)

AF:

0.00

AC:

AN:

39150

South Asian (SAS)

AF:

0.00

AC:

AN:

72080

European-Finnish (FIN)

AF:

0.0000210

AC:

AN:

47684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5368

European-Non Finnish (NFE)

AF:

0.000389

AC:

419

AN:

1077780

Other (OTH)

AF:

0.000265

AC:

AN:

56660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000427

AC:

AN:

67936

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000558

AC:

ExAC

AF:

0.000188

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6625G>C (p.A2209P) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a G to C substitution at nucleotide position 6625, causing the alanine (A) at amino acid position 2209 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.6

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.077

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.094

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-0.25

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.19

REVEL

Benign

0.10

Sift

Benign

0.31

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.12

MVP

0.59

ClinPred

0.10

GERP RS

-3.5

Varity_R

0.10

gMVP

0.097

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over