chrX-49226056-G-C

Position:

• chrX-49226056-G-C

Variant summary

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

The NM_001256789.3(CACNA1F):​c.1504C>G​(p.Arg502Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.608

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.1504C>G	p.Arg502Gly	missense_variant	13/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1537C>G	p.Arg513Gly	missense_variant	13/48		NP_005174.2
CACNA1F	NM_001256790.3	c.1342C>G	p.Arg448Gly	missense_variant	13/48		NP_001243719.1
CACNA1F	XM_011543983.3	c.1342C>G	p.Arg448Gly	missense_variant	13/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1504C>G	p.Arg502Gly	missense_variant	13/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.1537C>G	p.Arg513Gly	missense_variant	13/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.1342C>G	p.Arg448Gly	missense_variant	13/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111437 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33637

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111437 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33637

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Jun 02, 2020

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 arginine with glycine at codon 513 of the CACNA1F protein (p.Arg513Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Uncertain	0.72	.;.;D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.1	.;.;M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.96	.;.;D
Vest4		0.29
MutPred		0.48		.;.;Loss of helix (P = 0.0104);
MVP		0.87
MPC		0.94
ClinPred		0.99	D
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1365490247; hg19: chrX-49082518;