Genetic Variant CACNA1F:p.Arg262Gly (chrX-49230253-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001256789.3(CACNA1F):c.784C>G(p.Arg262Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

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: 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

CACNA1F links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CACNA1F	NM_001256789.3 link	c.784C>G	p.Arg262Gly	missense_variant	Exon 6 of 48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4 link	c.784C>G	p.Arg262Gly	missense_variant	Exon 6 of 48		NP_005174.2
CACNA1F	NM_001256790.3 link	c.589C>G	p.Arg197Gly	missense_variant	Exon 6 of 48		NP_001243719.1
CACNA1F	XM_011543983.3 link	c.589C>G	p.Arg197Gly	missense_variant	Exon 6 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1F	ENST00000323022.10 link	c.784C>G	p.Arg262Gly	missense_variant	Exon 6 of 48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2 link	c.784C>G	p.Arg262Gly	missense_variant	Exon 6 of 48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5 link	c.589C>G	p.Arg197Gly	missense_variant	Exon 6 of 48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1093245

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359089

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26331

American (AMR)

AF:

0.00

AC:

AN:

34783

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19284

East Asian (EAS)

AF:

0.00

AC:

AN:

30070

South Asian (SAS)

AF:

0.00

AC:

AN:

53228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40249

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839270

Other (OTH)

AF:

0.00

AC:

AN:

45906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;.;D

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

.;L;L

PhyloP100

0.30

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.027

D;D;D

Polyphen

0.98

.;.;D

Vest4

0.61

MutPred

0.74

.;Loss of methylation at R262 (P = 0.0336);Loss of methylation at R262 (P = 0.0336);

MVP

0.98

MPC

0.95

ClinPred

0.98

GERP RS

4.0

Varity_R

0.76

gMVP

0.93

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over