X-49205282-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256789.3(CACNA1F):c.5756G>C(p.Arg1919Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1919H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19984403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1F	NM_001256789.3	c.5756G>C	p.Arg1919Pro	missense_variant	48/48	ENST00000323022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1F	ENST00000323022.10	c.5756G>C	p.Arg1919Pro	missense_variant	48/48	1	NM_001256789.3
CACNA1F	ENST00000376265.2	c.5789G>C	p.Arg1930Pro	missense_variant	48/48	1		P1
CACNA1F	ENST00000376251.5	c.5594G>C	p.Arg1865Pro	missense_variant	48/48	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000554 AC: 1 AN: 180387 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65277

Gnomad AFR exome AF: 0.0000772

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096495 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361913

Gnomad4 AFR exome AF: 0.0000379

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.95	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.023
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.34	.;.;B
Vest4		0.36
MutPred		0.44		.;.;Gain of loop (P = 0.0312);
MVP		0.37
MPC		0.34
ClinPred		0.25	T
GERP RS		1.1
Varity_R		0.43
gMVP		0.92

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: rs33910054; hg19: chrX-49061742;