rs1557110046

Variant names:

• chrX-49226673-T-TA
• rs1557110046
• NM_001256789.3:c.1305_1306insT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3_Moderate PP5

The NM_001256789.3(CACNA1F):​c.1305_1306insT​(p.Arg436fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CACNA1F NM_001256789.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.40
• Publications: 0 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 13 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-49226673-T-TA is Pathogenic according to our data. Variant chrX-49226673-T-TA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438119.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.1305_1306insT	p.Arg436fs	frameshift_variant	Exon 10 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1338_1339insT	p.Arg447fs	frameshift_variant	Exon 10 of 48		NP_005174.2
CACNA1F	NM_001256790.3	c.1143_1144insT	p.Arg382fs	frameshift_variant	Exon 10 of 48		NP_001243719.1
CACNA1F	XM_011543983.3	c.1143_1144insT	p.Arg382fs	frameshift_variant	Exon 10 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1305_1306insT	p.Arg436fs	frameshift_variant	Exon 10 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.1338_1339insT	p.Arg447fs	frameshift_variant	Exon 10 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.1143_1144insT	p.Arg382fs	frameshift_variant	Exon 10 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: 2

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

Other links and lift over

dbSNP: rs1557110046; hg19: chrX-49083135;