rs1365490247

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001256789.3(CACNA1F):c.1504C>T(p.Arg502*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,075,845 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

CACNA1F
NM_001256789.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.608

Publications

2 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-49226056-G-A is Pathogenic according to our data. Variant chrX-49226056-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 497205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CACNA1F	NM_001256789.3 link	c.1504C>T	p.Arg502*	stop_gained	Exon 13 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4 link	c.1537C>T	p.Arg513*	stop_gained	Exon 13 of 48		NP_005174.2
CACNA1F	NM_001256790.3 link	c.1342C>T	p.Arg448*	stop_gained	Exon 13 of 48		NP_001243719.1
CACNA1F	XM_011543983.3 link	c.1342C>T	p.Arg448*	stop_gained	Exon 13 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1F	ENST00000323022.10 link	c.1504C>T	p.Arg502*	stop_gained	Exon 13 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2 link	c.1537C>T	p.Arg513*	stop_gained	Exon 13 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5 link	c.1342C>T	p.Arg448*	stop_gained	Exon 13 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111437

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000706

AC:

AN:

141673

AF XY:

0.0000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.30e-7

AC:

AN:

1075845

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349579

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25853

American (AMR)

AF:

0.00

AC:

AN:

31843

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18977

East Asian (EAS)

AF:

0.00

AC:

AN:

28934

South Asian (SAS)

AF:

0.00

AC:

AN:

51492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38911

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

830535

Other (OTH)

AF:

0.00

AC:

AN:

45206

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000897

AC:

AN:

111437

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33637

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30594

American (AMR)

AF:

0.00

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3518

South Asian (SAS)

AF:

0.000377

AC:

AN:

2652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6077

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52987

Other (OTH)

AF:

0.00

AC:

AN:

1489

Age Distribution

Genome Hom

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:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Sep 21, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25307992, 28559085, 32037395, 26992781) -

Apr 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with cone-rod dystrophy and/or congenital stationary night blindness (PMID: 26992781, 28002560). ClinVar contains an entry for this variant (Variation ID: 497205). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg513*) in the CACNA1F gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1F are known to be pathogenic (PMID: 9662399, 11281458, 17525176, 22194652, 24124559, 26992781). -

May 21, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Feb 21, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.33

PhyloP100

0.61

Vest4

0.85

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over