rs781923569

Positions:

• chrX-49231744-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001256789.3(CACNA1F):​c.209G>A​(p.Arg70Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,097,683 control chromosomes in the GnomAD database, including 1 homozygotes. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000030 (1 hom. 10 hem.)
• Consequence: CACNA1F NM_001256789.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.80

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 Benign. Variant got -9 ACMG points.

• BP6: Variant X-49231744-C-T is Benign according to our data. Variant chrX-49231744-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191248.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000301 (33/1097683) while in subpopulation MID AF= 0.00339 (14/4126). AF 95% confidence interval is 0.00205. There are 1 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3	c.209G>A	p.Arg70Gln	missense_variant	2/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4	c.209G>A	p.Arg70Gln	missense_variant	2/48		NP_005174.2
CACNA1F	NM_001256790.3	c.66-52G>A		intron_variant			NP_001243719.1
CACNA1F	XM_011543983.3	c.66-52G>A		intron_variant			XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10	c.209G>A	p.Arg70Gln	missense_variant	2/48	1	NM_001256789.3	ENSP00000321618
CACNA1F	ENST00000376265.2	c.209G>A	p.Arg70Gln	missense_variant	2/48	1		ENSP00000365441	P1
CACNA1F	ENST00000376251.5	c.66-52G>A		intron_variant		1		ENSP00000365427

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000274 AC: 5 AN: 182563 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67283

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000491

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1097683 Hom.: 1 Cov.: 31 AF XY: 0.0000275 AC XY: 10 AN XY: 363065

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 191248). This variant has not been reported in the literature in individuals affected with CACNA1F-related conditions. This variant is present in population databases (rs781923569, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the CACNA1F protein (p.Arg70Gln). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.51
MutPred		0.46		Loss of MoRF binding (P = 0.0322);Loss of MoRF binding (P = 0.0322);
MVP		0.84
MPC		0.89
ClinPred		0.64	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.75

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: rs781923569; hg19: chrX-49088206; COSMIC: COSV100545354; COSMIC: COSV100545354;