NM_001256789.3:c.1504C>T

Variant names:

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
CACNA1F-related retinopathy
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256789.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1F	NM_001256789.3	MANE Select	c.1504C>T	p.Arg502*	stop_gained	Exon 13 of 48	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4		c.1537C>T	p.Arg513*	stop_gained	Exon 13 of 48	NP_005174.2	O60840-1
CACNA1F	NM_001256790.3		c.1342C>T	p.Arg448*	stop_gained	Exon 13 of 48	NP_001243719.1	O60840-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.1504C>T	p.Arg502*	stop_gained	Exon 13 of 48	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2	TSL:1	c.1537C>T	p.Arg513*	stop_gained	Exon 13 of 48	ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5	TSL:1	c.1342C>T	p.Arg448*	stop_gained	Exon 13 of 48	ENSP00000365427.1	O60840-4

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over