rs886044841

chrX-49219633-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_001256789.3(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 NM_001256789.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Splicing 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3	c.2543+1G>A		splice_donor_variant		ENST00000323022.10
CACNA1F	NM_001256790.3	c.2381+1G>A		splice_donor_variant
CACNA1F	NM_005183.4	c.2576+1G>A		splice_donor_variant
CACNA1F	XM_011543983.3	c.2381+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10	c.2543+1G>A		splice_donor_variant		1	NM_001256789.3
CACNA1F	ENST00000376251.5	c.2381+1G>A		splice_donor_variant		1
CACNA1F	ENST00000376265.2	c.2576+1G>A		splice_donor_variant		1		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000614 AC: 1 AN: 162946 Hom.: 0 AF XY: 0.0000193 AC XY: 1 AN XY: 51690

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: 3 AN: 1088971 Hom.: 0 Cov.: 33 AF XY: 0.00000561 AC XY: 2 AN XY: 356359

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.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

CACNA1F-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 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 patients/families with X-linked congenital stationary night blindness (CSNB) incomplete type 2A (Wang et al. 2017. PubMed ID: 28838317; Zeitz et al. 2019. PubMed ID: 30825406; Lodha et al. 2012. PubMed ID: 22183355). 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. -

Ocular albinism, type II;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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	34
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
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

Other links and lift over

dbSNP: rs886044841; hg19: chrX-49076092;