rs6520408

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.41C>T(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,175,821 control chromosomes in the GnomAD database, including 699 homozygotes. There are 3,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 350 hom., 1441 hem., cov: 23)

Exomes 𝑓: 0.0058 ( 349 hom. 1742 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.50

Publications

9 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=0.0013768077).

BP6

Variant X-49231912-G-A is Benign according to our data. Variant chrX-49231912-G-A is described in ClinVar as Benign. ClinVar VariationId is 166780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 2 of 48	ENST00000323022.10	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 2 of 48		NP_005174.2	O60840-1
CACNA1F	NM_001256790.3 link	c.66-220C>T		intron_variant	Intron 1 of 47		NP_001243719.1	O60840-4
CACNA1F	XM_011543983.3 link	c.66-220C>T		intron_variant	Intron 1 of 46		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1F	ENST00000323022.10 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 2 of 48	1	NM_001256789.3	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2 link	c.41C>T	p.Pro14Leu	missense_variant	Exon 2 of 48	1		ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5 link	c.66-220C>T		intron_variant	Intron 1 of 47	1		ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

AF:

0.0485

AC:

5443

AN:

112170

Hom.:

350

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.00150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000582

Gnomad OTH

AF:

0.0323

GnomAD2 exomes

AF:

0.0149

AC:

1869

AN:

125838

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.00826

Gnomad ASJ exome

AF:

0.000778

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000233

Gnomad OTH exome

AF:

0.00839

GnomAD4 exome

AF:

0.00585

AC:

6220

AN:

1063599

Hom.:

349

Cov.:

AF XY:

0.00504

AC XY:

1742

AN XY:

345867

show subpopulations

African (AFR)

AF:

0.178

AC:

4554

AN:

25633

American (AMR)

AF:

0.00984

AC:

288

AN:

29256

Ashkenazi Jewish (ASJ)

AF:

0.000640

AC:

AN:

18760

East Asian (EAS)

AF:

0.00

AC:

AN:

28392

South Asian (SAS)

AF:

0.0103

AC:

524

AN:

50750

European-Finnish (FIN)

AF:

0.0000816

AC:

AN:

36774

Middle Eastern (MID)

AF:

0.00587

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.000199

AC:

164

AN:

825127

Other (OTH)

AF:

0.0145

AC:

651

AN:

44821

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

223

446

668

891

1114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0487

AC:

5466

AN:

112222

Hom.:

350

Cov.:

AF XY:

0.0419

AC XY:

1441

AN XY:

34404

show subpopulations

African (AFR)

AF:

0.168

AC:

5174

AN:

30757

American (AMR)

AF:

0.0179

AC:

190

AN:

10633

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00622

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6181

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000582

AC:

AN:

53266

Other (OTH)

AF:

0.0319

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

160

321

481

642

802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0208

Hom.:

1037

Bravo

AF:

0.0567

ESP6500AA

AF:

0.162

AC:

614

ESP6500EA

AF:

0.000449

AC:

ExAC

AF:

0.0147

AC:

1659

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 16, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

.;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.90

L;L

PhyloP100

3.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.0020

.;B

Vest4

0.056

MPC

0.34

ClinPred

0.030

GERP RS

4.3

Varity_R

0.19

gMVP

0.56

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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