rs122456134

Variant names:

• chrX-49218511-G-A
• rs122456134
• NM_001256789.3:c.2872C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-49218511-G-A
• chrX-49218511-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001256789.3(CACNA1F):​c.2872C>T​(p.Arg958*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 1,077,004 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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: 21)
  • Exomes 𝑓: 0.0000056 (0 hom. 2 hem.)
• Consequence: CACNA1F NM_001256789.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.13
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• CACNA1F-related retinopathy

  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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-49218511-G-A is Pathogenic according to our data. Variant chrX-49218511-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256789.3. 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.2872C>T	p.Arg958*	stop_gained	Exon 24 of 48	NP_001243718.1	O60840-2
	CACNA1F	NM_005183.4		c.2905C>T	p.Arg969*	stop_gained	Exon 24 of 48	NP_005174.2	O60840-1
	CACNA1F	NM_001256790.3		c.2710C>T	p.Arg904*	stop_gained	Exon 24 of 48	NP_001243719.1	O60840-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.2872C>T	p.Arg958*	stop_gained	Exon 24 of 48	ENSP00000321618.6	O60840-2
	CACNA1F	ENST00000376265.2	TSL:1	c.2905C>T	p.Arg969*	stop_gained	Exon 24 of 48	ENSP00000365441.2	O60840-1
	CACNA1F	ENST00000376251.5	TSL:1	c.2710C>T	p.Arg904*	stop_gained	Exon 24 of 48	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000557 AC: 6 AN: 1077004 Hom.: 0 Cov.: 33 AF XY: 0.00000571 AC XY: 2 AN XY: 350434

African (AFR) AF: 0.00 AC: 0 AN: 26018

American (AMR) AF: 0.00 AC: 0 AN: 31910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18889

East Asian (EAS) AF: 0.00 AC: 0 AN: 29334

South Asian (SAS) AF: 0.00 AC: 0 AN: 51192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38417

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4085

European-Non Finnish (NFE) AF: 0.00000721 AC: 6 AN: 831795

Other (OTH) AF: 0.00 AC: 0 AN: 45364

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.1
Vest4		0.84
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs122456134; hg19: chrX-49074970; COSMIC: COSV100544544; COSMIC: COSV100544544;