rs1557110499

Positions:

• chrX-49228310-CGAA-C

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_954del​(p.Phe318del) variant causes a 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 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/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.952_954del	p.Phe318del	inframe_deletion	7/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_001256790.3	c.757_759del	p.Phe253del	inframe_deletion	7/48		NP_001243719.1
CACNA1F	NM_005183.4	c.952_954del	p.Phe318del	inframe_deletion	7/48		NP_005174.2
CACNA1F	XM_011543983.3	c.757_759del	p.Phe253del	inframe_deletion	7/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.952_954del	p.Phe318del	inframe_deletion	7/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376251.5	c.757_759del	p.Phe253del	inframe_deletion	7/48	1		ENSP00000365427
CACNA1F	ENST00000376265.2	c.952_954del	p.Phe318del	inframe_deletion	7/48	1		ENSP00000365441	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2022	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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438129). This variant has been observed in individuals with congenital stationary night blindness (PMID: 11281458, 23714322, 30825406; Invitae). It has also been observed to segregate with disease in related individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CACNA1F: PM2, PS4:Moderate, PM3:Supporting, PM4:Supporting -

Cone-rod dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Congenital stationary night blindness Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

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;