chrX-49226056-G-A

Position:

chrX-49226056-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001256789.3(CACNA1F):c.1504C>T(p.Arg502Ter) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id is 497205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49226056-G-A is described in Lovd as [Pathogenic]. Variant chrX-49226056-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA1F	NM_001256789.3 linkuse as main transcript	c.1504C>T	p.Arg502Ter	stop_gained	13/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4 linkuse as main transcript	c.1537C>T	p.Arg513Ter	stop_gained	13/48		NP_005174.2
CACNA1F	NM_001256790.3 linkuse as main transcript	c.1342C>T	p.Arg448Ter	stop_gained	13/48		NP_001243719.1
CACNA1F	XM_011543983.3 linkuse as main transcript	c.1342C>T	p.Arg448Ter	stop_gained	13/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10 linkuse as main transcript	c.1504C>T	p.Arg502Ter	stop_gained	13/48	1	NM_001256789.3	ENSP00000321618		O60840-2
CACNA1F	ENST00000376265.2 linkuse as main transcript	c.1537C>T	p.Arg513Ter	stop_gained	13/48	1		ENSP00000365441	P1	O60840-1
CACNA1F	ENST00000376251.5 linkuse as main transcript	c.1342C>T	p.Arg448Ter	stop_gained	13/48	1		ENSP00000365427		O60840-4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111437

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33637

FAILED QC

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

GnomAD3 exomes

AF:

0.00000706

AC:

AN:

141673

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

43599

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 SAS exome

AF:

0.0000640

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000120

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 03, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 497205). This premature translational stop signal has been observed in individual(s) with cone-rod dystrophy and/or congenital stationary night blindness (PMID: 26992781, 28002560). 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 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). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.33

MutationTaster

Benign

1.0

A;A;A

Vest4

0.85

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over