rs863225090

Positions:

• chrX-49219668-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001256789.3(CACNA1F):​c.2509G>A​(p.Gly837Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,092,980 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.14

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-49219668-C-T is Pathogenic according to our data. Variant chrX-49219668-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217443.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.2509G>A	p.Gly837Ser	missense_variant	20/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.2542G>A	p.Gly848Ser	missense_variant	20/48		NP_005174.2
CACNA1F	NM_001256790.3	c.2347G>A	p.Gly783Ser	missense_variant	20/48		NP_001243719.1
CACNA1F	XM_011543983.3	c.2347G>A	p.Gly783Ser	missense_variant	20/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.2509G>A	p.Gly837Ser	missense_variant	20/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.2542G>A	p.Gly848Ser	missense_variant	20/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.2347G>A	p.Gly783Ser	missense_variant	20/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092980 Hom.: 0 Cov.: 33 AF XY: 0.00000278 AC XY: 1 AN XY: 359200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked cone-rod dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 11, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.9	.;.;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.90	.;.;P
Vest4		0.45
MutPred		0.47		.;.;Loss of sheet (P = 0.0315);
MVP		0.95
MPC		0.53
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.76
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

LitVar

Other links and lift over

dbSNP: rs863225090; hg19: chrX-49076127;