X-49215088-G-A

Position:

• chrX-49215088-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1 PP3_Moderate PP5 BS2_Supporting

The NM_001256789.3(CACNA1F):​c.3595C>T​(p.Gln1199Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,371 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: CACNA1F NM_001256789.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.07

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-49215088-G-A is Pathogenic according to our data. Variant chrX-49215088-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438125.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-49215088-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.3595C>T	p.Gln1199Ter	stop_gained, splice_region_variant	29/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.3595C>T	p.Gln1199Ter	stop_gained, splice_region_variant	29/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.3628C>T	p.Gln1210Ter	stop_gained, splice_region_variant	29/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.3433C>T	p.Gln1145Ter	stop_gained, splice_region_variant	29/48	1		ENSP00000365427

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096371 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 2 AN XY: 361785

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Abnormality of the eye Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

Undetermined rare ocular disorder with frequency of less than eight patients -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	60
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.97
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 2
DS_DL_spliceai		0.76		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs782362725; hg19: chrX-49071548; COSMIC: COSV59903891; COSMIC: COSV59903891;