X-49228048-C-T

Position:

• chrX-49228048-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001256789.3(CACNA1F):​c.1106G>A​(p.Gly369Asp) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.85

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-49228048-C-T is Pathogenic according to our data. Variant chrX-49228048-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11614.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-49228048-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.1106G>A	p.Gly369Asp	missense_variant	8/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.1106G>A	p.Gly369Asp	missense_variant	8/48		NP_005174.2
CACNA1F	NM_001256790.3	c.911G>A	p.Gly304Asp	missense_variant	8/48		NP_001243719.1
CACNA1F	XM_011543983.3	c.911G>A	p.Gly304Asp	missense_variant	8/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.1106G>A	p.Gly369Asp	missense_variant	8/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.1106G>A	p.Gly369Asp	missense_variant	8/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.911G>A	p.Gly304Asp	missense_variant	8/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital stationary night blindness 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	.;H;H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.95
MutPred		0.95		.;Loss of catalytic residue at V370 (P = 0.0386);Loss of catalytic residue at V370 (P = 0.0386);
MVP		1.0
MPC		0.96
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs122456133; hg19: chrX-49084510;