rs80359870

Positions:

• chrX-49216484-A-AG

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.3133dupC​(p.Leu1045fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CACNA1F NM_001256789.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.690

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-49216484-A-AG is Pathogenic according to our data. Variant chrX-49216484-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 21443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.3133dupC	p.Leu1045fs	frameshift_variant	27/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.3133dupC	p.Leu1045fs	frameshift_variant	27/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.3166dupC	p.Leu1056fs	frameshift_variant	27/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.2971dupC	p.Leu991fs	frameshift_variant	27/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091354 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 357276

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: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Leu1056Profs*11) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked congenital stationary night blindness (PMID: 9662399, 9662400, 10900517). It is commonly reported in individuals of Mennonite ancestry (PMID: 9662399, 9662400, 10900517). This variant is also known as 3133inC, Leu991insC, and Leu1056insC. ClinVar contains an entry for this variant (Variation ID: 21443). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Common pathogenic variant among individuals of Dutch-German Mennonite background (Bech-Hansen et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); Also known as L991insC using alternate nomenclature; This variant is associated with the following publications: (PMID: 9662399, 28162000, 10900517, 18348259, 22744390, 33668843, 20301423, 9662400) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Congenital stationary night blindness 2A Pathogenic:4

Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 26, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 30, 2024	Criteria applied: PVS1,PS4_MOD,PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 08, 2022	- -

CACNA1F-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2023

The CACNA1F c.3166dupC variant is predicted to result in a frameshift and premature protein termination (p.Leu1056Profs*11). This variant has been reported in multiple individuals with congenital stationary night blindness (see for example Vincent and Héon et al. 2012. PubMed ID: 22744390; reported as c.3133insC in Strom et al. 1998. PubMed ID: 9662399). Frameshift variants in CACNA1F are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/21443). Given all the evidence, we interpret c.3166dup (p.Leu1056Profs*11) as pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jan 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs80359870; hg19: chrX-49072944;