X-49205282-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256789.3(CACNA1F):c.5756G>A(p.Arg1919His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,206,688 control chromosomes in the GnomAD database, including 3,568 homozygotes. There are 36,726 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1919R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.067 ( 252 hom., 2164 hem., cov: 22)

Exomes 𝑓: 0.090 ( 3316 hom. 34562 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 1.47

Publications

23 publications found

Variant links:

Genes affected

CACNA1F (HGNC:1393): (calcium voltage-gated channel subunit alpha1 F) This gene encodes a multipass transmembrane protein that functions as an alpha-1 subunit of the voltage-dependent calcium channel, which mediates the influx of calcium ions into the cell. The encoded protein forms a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2013]

CACNA1F Gene-Disease associations (from GenCC):

Aland island eye disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
inherited retinal dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
congenital stationary night blindness 2A
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
X-linked cone-rod dystrophy 3
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1F links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017129481).

BP6

Variant X-49205282-C-T is Benign according to our data. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49205282-C-T is described in CliVar as Benign. Clinvar id is 100576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3 link	c.5756G>A	p.Arg1919His	missense_variant	Exon 48 of 48	ENST00000323022.10	NP_001243718.1	O60840-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1F	ENST00000323022.10 link	c.5756G>A	p.Arg1919His	missense_variant	Exon 48 of 48	1	NM_001256789.3	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2 link	c.5789G>A	p.Arg1930His	missense_variant	Exon 48 of 48	1		ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5 link	c.5594G>A	p.Arg1865His	missense_variant	Exon 48 of 48	1		ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

AF:

0.0668

AC:

7369

AN:

110233

Hom.:

252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.00590

Gnomad AMR

AF:

0.0536

Gnomad ASJ

AF:

0.0782

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.0744

Gnomad MID

AF:

0.0297

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0979

AC:

17653

AN:

180387

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.0680

Gnomad ASJ exome

AF:

0.0761

Gnomad EAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.0826

Gnomad NFE exome

AF:

0.0811

Gnomad OTH exome

AF:

0.0843

GnomAD4 exome

AF:

0.0903

AC:

99025

AN:

1096402

Hom.:

3316

Cov.:

AF XY:

0.0955

AC XY:

34562

AN XY:

361860

show subpopulations

African (AFR)

AF:

0.0214

AC:

565

AN:

26383

American (AMR)

AF:

0.0659

AC:

2314

AN:

35105

Ashkenazi Jewish (ASJ)

AF:

0.0754

AC:

1459

AN:

19358

East Asian (EAS)

AF:

0.192

AC:

5790

AN:

30168

South Asian (SAS)

AF:

0.219

AC:

11843

AN:

53984

European-Finnish (FIN)

AF:

0.0831

AC:

3354

AN:

40381

Middle Eastern (MID)

AF:

0.0610

AC:

252

AN:

4133

European-Non Finnish (NFE)

AF:

0.0824

AC:

69316

AN:

840849

Other (OTH)

AF:

0.0897

AC:

4132

AN:

46041

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3376

6752

10129

13505

16881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2762

5524

8286

11048

13810

<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:

0.0668

AC:

7362

AN:

110286

Hom.:

252

Cov.:

AF XY:

0.0664

AC XY:

2164

AN XY:

32578

show subpopulations

African (AFR)

AF:

0.0208

AC:

633

AN:

30411

American (AMR)

AF:

0.0540

AC:

560

AN:

10365

Ashkenazi Jewish (ASJ)

AF:

0.0782

AC:

206

AN:

2635

East Asian (EAS)

AF:

0.185

AC:

631

AN:

3405

South Asian (SAS)

AF:

0.220

AC:

570

AN:

2592

European-Finnish (FIN)

AF:

0.0744

AC:

429

AN:

5769

Middle Eastern (MID)

AF:

0.0279

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0801

AC:

4226

AN:

52727

Other (OTH)

AF:

0.0651

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

233

465

698

930

1163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0755

Hom.:

4779

Bravo

AF:

0.0614

TwinsUK

AF:

0.0790

AC:

293

ALSPAC

AF:

0.0848

AC:

245

ESP6500AA

AF:

0.0214

AC:

ESP6500EA

AF:

0.0846

AC:

569

ExAC

AF:

0.103

AC:

12483

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

May 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.051

.;.;T

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.99

.;.;N

PhyloP100

1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.23

N;N;N

REVEL

Benign

0.051

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.031

MPC

0.28

ClinPred

0.013

GERP RS

1.1

Varity_R

0.044

gMVP

0.65

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over