rs80359870

Variant names:

• chrX-49216484-A-AG
• rs80359870
• NM_001256789.3:c.3133dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005183.4(CACNA1F):​c.3166dupC​(p.Leu1056ProfsTer11) 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_005183.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.690
• Publications: 5 publications found

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]

CACNA1F Gene-Disease associations (from GenCC):

• Aland island eye disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• inherited retinal dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness 2A

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked cone-rod dystrophy 3

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 21443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005183.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	NM_001256789.3	MANE Select	c.3133dupC	p.Leu1045ProfsTer11	frameshift	Exon 27 of 48	NP_001243718.1
	CACNA1F	NM_005183.4		c.3166dupC	p.Leu1056ProfsTer11	frameshift	Exon 27 of 48	NP_005174.2
	CACNA1F	NM_001256790.3		c.2971dupC	p.Leu991ProfsTer11	frameshift	Exon 27 of 48	NP_001243719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.3133dupC	p.Leu1045ProfsTer11	frameshift	Exon 27 of 48	ENSP00000321618.6
	CACNA1F	ENST00000376265.2	TSL:1	c.3166dupC	p.Leu1056ProfsTer11	frameshift	Exon 27 of 48	ENSP00000365441.2
	CACNA1F	ENST00000376251.5	TSL:1	c.2971dupC	p.Leu991ProfsTer11	frameshift	Exon 27 of 48	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

African (AFR) AF: 0.00 AC: 0 AN: 26328

American (AMR) AF: 0.00 AC: 0 AN: 34527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19249

East Asian (EAS) AF: 0.00 AC: 0 AN: 30099

South Asian (SAS) AF: 0.00 AC: 0 AN: 52982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838047

Other (OTH) AF: 0.0000218 AC: 1 AN: 45870

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Congenital stationary night blindness 2A (4)
1	-	-	CACNA1F-related disorder (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80359870; hg19: chrX-49072944;