rs1557110499

Variant names:

• chrX-49228310-CGAA-C
• rs1557110499
• NM_001256789.3:c.952_954delTTC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001256789.3(CACNA1F):​c.952_954delTTC​(p.Phe318del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,593 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CACNA1F NM_001256789.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.41

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001256789.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-49228310-CGAA-C is Pathogenic according to our data. Variant chrX-49228310-CGAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49228310-CGAA-C is described in Lovd as [Pathogenic]. Variant chrX-49228310-CGAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.952_954delTTC	p.Phe318del	conservative_inframe_deletion	Exon 7 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.952_954delTTC	p.Phe318del	conservative_inframe_deletion	Exon 7 of 48		NP_005174.2
CACNA1F	NM_001256790.3	c.757_759delTTC	p.Phe253del	conservative_inframe_deletion	Exon 7 of 48		NP_001243719.1
CACNA1F	XM_011543983.3	c.757_759delTTC	p.Phe253del	conservative_inframe_deletion	Exon 7 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.952_954delTTC	p.Phe318del	conservative_inframe_deletion	Exon 7 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.952_954delTTC	p.Phe318del	conservative_inframe_deletion	Exon 7 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.757_759delTTC	p.Phe253del	conservative_inframe_deletion	Exon 7 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097593 Hom.: 0 AF XY: 0.00000276 AC XY: 1 AN XY: 362963

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.952_954del, results in the deletion of 1 amino acid(s) of the CACNA1F protein (p.Phe318del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with congenital stationary night blindness (PMID: 11281458, 23714322, 30825406; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438129). For these reasons, this variant has been classified as Pathogenic. -

Sep 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23714322, 11281458, 32581362, 30825406) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1F: PM2, PS4:Moderate, PM3:Supporting, PM4:Supporting -

Cone-rod dystrophy Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Congenital stationary night blindness Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1557110499; hg19: chrX-49084772;