Genetic Variant NM_001256789.3:c.2289-2_2289delAGGinsCGA (chrX-49221080-CCT-TCG) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is . The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001256789.3(CACNA1F):c.2289-2_2289delAGGinsCGA(p.764) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Consequence

CACNA1F
NM_001256789.3 splice_acceptor, splice_region, synonymous, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

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

CACNA1F links:

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new If you want to explore the variant's impact on the transcript NM_001256789.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.2, offset of -25, new splice context is: ctcccttagcccatctgcAGcaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1F	NM_001256789.3	MANE Select	c.2289-2_2289delAGGinsCGA	p.764	splice_acceptor splice_region synonymous intron	N/A	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4		c.2322-2_2322delAGGinsCGA	p.775	splice_acceptor splice_region synonymous intron	N/A	NP_005174.2	O60840-1
CACNA1F	NM_001256790.3		c.2127-2_2127delAGGinsCGA	p.710	splice_acceptor splice_region synonymous intron	N/A	NP_001243719.1	O60840-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1F	ENST00000323022.10	TSL:1 MANE Select	c.2289-2_2289delAGGinsCGA	p.764	splice_acceptor splice_region synonymous intron	N/A	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2	TSL:1	c.2322-2_2322delAGGinsCGA	p.775	splice_acceptor splice_region synonymous intron	N/A	ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5	TSL:1	c.2127-2_2127delAGGinsCGA	p.710	splice_acceptor splice_region synonymous intron	N/A	ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over