X-49205164-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001256789.3(CACNA1F):c.5874C>G(p.Asp1958Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,095,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1958D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 0 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35553822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3 linkuse as main transcript	c.5874C>G	p.Asp1958Glu	missense_variant	48/48	ENST00000323022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10 linkuse as main transcript	c.5874C>G	p.Asp1958Glu	missense_variant	48/48	1	NM_001256789.3		O60840-2
CACNA1F	ENST00000376265.2 linkuse as main transcript	c.5907C>G	p.Asp1969Glu	missense_variant	48/48	1		P1	O60840-1
CACNA1F	ENST00000376251.5 linkuse as main transcript	c.5712C>G	p.Asp1904Glu	missense_variant	48/48	1			O60840-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000550

AC:

AN:

181656

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1095816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361310

show subpopulations

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:

0.00000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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 submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1969 of the CACNA1F protein (p.Asp1969Glu). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with CACNA1F-related conditions. ClinVar contains an entry for this variant (Variation ID: 1961526). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

Cadd

Benign

6.2

Dann

Uncertain

0.98

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Pathogenic

0.86

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.026

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.33

MutPred

0.40

.;.;Gain of disorder (P = 0.1256);

MVP

0.85

MPC

0.69

ClinPred

0.60

GERP RS

-3.6

Varity_R

0.17

gMVP

0.82

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over