rs122456134

chrX-49218511-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001256789.3(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 NM_001256789.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 16 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].

Transcripts

RefSeq

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

Ensembl

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

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital stationary night blindness 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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;