rs797044562

Positions:

• chrX-49217759-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PP3_Moderate BP6_Moderate

The NM_001256789.3(CACNA1F):​c.3085T>C​(p.Cys1029Arg) variant causes a missense change. 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.15

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.

• PM1: In a repeat III (size 282) in uniprot entity CAC1F_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001256789.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• BP6: Variant X-49217759-A-G is Benign according to our data. Variant chrX-49217759-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 191247.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.3085T>C	p.Cys1029Arg	missense_variant	26/48	ENST00000323022.10	NP_001243718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.3085T>C	p.Cys1029Arg	missense_variant	26/48	1	NM_001256789.3	ENSP00000321618.6
CACNA1F	ENST00000376265.2	c.3118T>C	p.Cys1040Arg	missense_variant	26/48	1		ENSP00000365441.2
CACNA1F	ENST00000376251.5	c.2923T>C	p.Cys975Arg	missense_variant	26/48	1		ENSP00000365427.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 28, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.73
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.85
MutPred		0.69		.;.;Gain of disorder (P = 0.0054);
MVP		0.99
MPC		0.79
ClinPred		0.86	D
GERP RS		4.6
Varity_R		0.97
gMVP		1.0

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: rs797044562; hg19: chrX-49074218;