rs122456134

Positions:

• chrX-49218511-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The ENST00000323022.10(CACNA1F):​c.2872C>T​(p.Arg958Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 1,077,004 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. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000056 (0 hom. 2 hem.)
• Consequence: CACNA1F ENST00000323022.10 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.13

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 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-49218511-G-A is Pathogenic according to our data. Variant chrX-49218511-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49218511-G-A is described in Lovd as [Pathogenic]. Variant chrX-49218511-G-A is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.2872C>T	p.Arg958Ter	stop_gained	24/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.2872C>T	p.Arg958Ter	stop_gained	24/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.2905C>T	p.Arg969Ter	stop_gained	24/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.2710C>T	p.Arg904Ter	stop_gained	24/48	1		ENSP00000365427

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000557 AC: 6 AN: 1077004 Hom.: 0 Cov.: 33 AF XY: 0.00000571 AC XY: 2 AN XY: 350434

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: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital stationary night blindness 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Apr 12, 2024	The CACNA1F c.2872C>T (p.Arg958*) variant has been observed in at least two individuals or families affected with X-linked congenital stationary night blindness, defined as either reduced visual acuity, nystagmus, strabismus, or a combination of these findings (Strom TM et al., PMID: 9662399; Zeitz C et al., PMID: 25307992). Furthermore, this variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Additionally, other variants that introduce premature termination codons in this region have been described in affected individuals and are considered pathogenic (Wutz K et al., PMID: 12111638). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -

CACNA1F-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The CACNA1F c.2905C>T variant is predicted to result in premature protein termination (p.Arg969*). This variant has been reported in a kindred with incomplete congenital stationary night blindness (reported as 2172C>T, R958X in Strom et al. 1998. PubMed ID: 9662399) and in an individual with reduced visual acuity and nystagmus (Thomas et al. 2017. PubMed ID: 28378818). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CACNA1F are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 11615). This variant is also known as p.Arg958*. This premature translational stop signal has been observed in individual(s) with incomplete congenital stationary night blindness (PMID: 9662399). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg969*) 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

Oct 30, 2018

- -

Congenital stationary night blindness Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.84
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs122456134; hg19: chrX-49074970; COSMIC: COSV100544544; COSMIC: COSV100544544;