X-49205216-T-G

Position:

• chrX-49205216-T-G

Variant summary

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

The NM_001256789.3(CACNA1F):​c.5822A>C​(p.Tyr1941Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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	Protein	UniProt
CACNA1F	NM_001256789.3	c.5822A>C	p.Tyr1941Ser	missense_variant	48/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5822A>C	p.Tyr1941Ser	missense_variant	48/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.5855A>C	p.Tyr1952Ser	missense_variant	48/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.5660A>C	p.Tyr1887Ser	missense_variant	48/48	1		ENSP00000365427

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1F-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 1952 of the CACNA1F protein (p.Tyr1952Ser). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.26	.;.;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.9	.;.;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.024	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.42	.;.;B
Vest4		0.41
MutPred		0.32		.;.;Gain of helix (P = 0.0143);
MVP		0.91
MPC		0.33
ClinPred		0.49	T
GERP RS		3.9
Varity_R		0.24
gMVP		0.86

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-49061676;