X-49223081-T-A

Position:

• chrX-49223081-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001256789.3(CACNA1F):​c.1933A>T​(p.Ile645Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.96

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.1933A>T	p.Ile645Phe	missense_variant	15/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1966A>T	p.Ile656Phe	missense_variant	15/48		NP_005174.2
CACNA1F	NM_001256790.3	c.1771A>T	p.Ile591Phe	missense_variant	15/48		NP_001243719.1
CACNA1F	XM_011543983.3	c.1771A>T	p.Ile591Phe	missense_variant	15/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1933A>T	p.Ile645Phe	missense_variant	15/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.1966A>T	p.Ile656Phe	missense_variant	15/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.1771A>T	p.Ile591Phe	missense_variant	15/48	1		ENSP00000365427
CACNA1F	ENST00000480889.1	n.63A>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked cone-rod dystrophy 3;C1848172:Congenital stationary night blindness 2A Uncertain:1

Uncertain significance, no assertion criteria provided

research

Tolun Lab, Human Genetics Laboratory, Bogazici University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.76
MutPred		0.76		.;.;Loss of catalytic residue at L661 (P = 0.0742);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.99

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

Other links and lift over

dbSNP: rs1344295491; hg19: chrX-49079540;