X-49205211-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001256789.3(CACNA1F):c.5827G>C(p.Asp1943His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1943N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3	c.5827G>C	p.Asp1943His	missense_variant	48/48	ENST00000323022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5827G>C	p.Asp1943His	missense_variant	48/48	1	NM_001256789.3
CACNA1F	ENST00000376265.2	c.5860G>C	p.Asp1954His	missense_variant	48/48	1		P1
CACNA1F	ENST00000376251.5	c.5665G>C	p.Asp1889His	missense_variant	48/48	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1954 of the CACNA1F protein (p.Asp1954His). This variant is not present in population databases (gnomAD no frequency). 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: 1719128). 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 tolerated. 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.30
MutPred		0.30		.;.;Loss of stability (P = 0.1161);
MVP		0.81
MPC		0.38
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49061671;