rs886044841

Positions:

chrX-49219633-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000323022.10(CACNA1F):c.2543+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000275 in 1,088,971 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Consequence

CACNA1F
ENST00000323022.10 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.97

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 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.5, offset of 23, new splice context is: gggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant X-49219633-C-T is Pathogenic according to our data. Variant chrX-49219633-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 285396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49219633-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CACNA1F	NM_001256789.3 linkuse as main transcript	c.2543+1G>A	splice_donor_variant	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_001256790.3 linkuse as main transcript	c.2381+1G>A	splice_donor_variant		NP_001243719.1
CACNA1F	NM_005183.4 linkuse as main transcript	c.2576+1G>A	splice_donor_variant		NP_005174.2
CACNA1F	XM_011543983.3 linkuse as main transcript	c.2381+1G>A	splice_donor_variant		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10 linkuse as main transcript	c.2543+1G>A	splice_donor_variant	1	NM_001256789.3	ENSP00000321618		O60840-2
CACNA1F	ENST00000376251.5 linkuse as main transcript	c.2381+1G>A	splice_donor_variant	1		ENSP00000365427		O60840-4
CACNA1F	ENST00000376265.2 linkuse as main transcript	c.2576+1G>A	splice_donor_variant	1		ENSP00000365441	P1	O60840-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000614

AC:

AN:

162946

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

51690

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1088971

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

356359

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:

0.00000358

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2023	This sequence change affects a donor splice site in intron 20 of the CACNA1F gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1F are known to be pathogenic (PMID: 9662399, 11281458, 17525176, 22194652, 24124559, 26992781). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with congenital stationary night blindness (PMID: 22183355, 28838317, 30825406). ClinVar contains an entry for this variant (Variation ID: 285396). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28838317, 30825406, 22183355, 33668843) -

Aland island eye disease;C1845407:X-linked cone-rod dystrophy 3;C1848172:Congenital stationary night blindness 2A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 10, 2021

- -

CACNA1F-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

The CACNA1F c.2576+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with congenital stationary night blindness (Wang et al. 2017. PubMed ID: 28838317; Zeitz et al. 2019. PubMed ID: 30825406; Lodha et al. 2012. PubMed ID: 22183355; Leahy et al. 2021. PubMed ID: 33668843). This variant is reported in 0.0014% of alleles in individuals of European (non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CACNA1F are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

D;D;D

GERP RS

5.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.67

Position offset: -22

DS_DL_spliceai

0.88

Position offset: 1

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