rs782581701

Positions:

• chrX-49210604-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001256789.3(CACNA1F):​c.4471C>T​(p.Arg1491*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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: 23)
• Consequence: CACNA1F NM_001256789.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.98

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 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-49210604-G-A is Pathogenic according to our data. Variant chrX-49210604-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 587382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49210604-G-A is described in Lovd as [Pathogenic]. Variant chrX-49210604-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.4471C>T	p.Arg1491*	stop_gained	38/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.4471C>T	p.Arg1491*	stop_gained	38/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.4504C>T	p.Arg1502*	stop_gained	38/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.4309C>T	p.Arg1437*	stop_gained	38/48	1		ENSP00000365427.1
CACNA1F	ENST00000481035.1	n.396C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Cone-rod dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Congenital stationary night blindness 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Aug 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.95
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs782581701; hg19: chrX-49067064;