chrX-49205151-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001256789.3(CACNA1F):​c.5887G>A​(p.Val1963Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000732 in 1,092,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000073 ( 0 hom. 4 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06943986).
BS2
High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CACNA1FNM_001256789.3 linkuse as main transcriptc.5887G>A p.Val1963Ile missense_variant 48/48 ENST00000323022.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CACNA1FENST00000323022.10 linkuse as main transcriptc.5887G>A p.Val1963Ile missense_variant 48/481 NM_001256789.3 O60840-2
CACNA1FENST00000376265.2 linkuse as main transcriptc.5920G>A p.Val1974Ile missense_variant 48/481 P1O60840-1
CACNA1FENST00000376251.5 linkuse as main transcriptc.5725G>A p.Val1909Ile missense_variant 48/481 O60840-4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
180966
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
65832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000366
Gnomad ASJ exome
AF:
0.000134
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000732
AC:
8
AN:
1092959
Hom.:
0
Cov.:
29
AF XY:
0.0000112
AC XY:
4
AN XY:
358689
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
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:
0.00000716
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
Bravo
AF:
0.0000340
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 03, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CACNA1F-related conditions. This variant is present in population databases (rs782793473, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1974 of the CACNA1F protein (p.Val1974Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
7.4
DANN
Benign
0.75
DEOGEN2
Benign
0.049
.;.;T
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.70
T;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.069
T;T;T
MetaSVM
Uncertain
0.095
D
MutationAssessor
Benign
-1.2
.;.;N
MutationTaster
Benign
0.97
D;D;D
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.14
N;N;N
REVEL
Benign
0.18
Sift
Benign
0.65
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.026
.;.;B
Vest4
0.12
MutPred
0.27
.;.;Loss of catalytic residue at V1974 (P = 0.0844);
MVP
0.65
MPC
0.38
ClinPred
0.032
T
GERP RS
2.3
Varity_R
0.084
gMVP
0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782793473; hg19: chrX-49061611; API