rs34162630

Positions:

chrX-49226037-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001256789.3(CACNA1F):c.1523G>A(p.Arg508Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,188,489 control chromosomes in the GnomAD database, including 258 homozygotes. There are 9,016 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 28 hom., 576 hem., cov: 23)

Exomes 𝑓: 0.024 ( 230 hom. 8440 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.83

Variant links:

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]

CACNA1F links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02172777).

BP6

Variant X-49226037-C-T is Benign according to our data. Variant chrX-49226037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49226037-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0174 (1935/110942) while in subpopulation NFE AF= 0.0262 (1385/52829). AF 95% confidence interval is 0.0251. There are 28 homozygotes in gnomad4. There are 576 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA1F	NM_001256789.3 linkuse as main transcript	c.1523G>A	p.Arg508Gln	missense_variant	13/48	ENST00000323022.10	NP_001243718.1
CACNA1F	NM_005183.4 linkuse as main transcript	c.1556G>A	p.Arg519Gln	missense_variant	13/48		NP_005174.2
CACNA1F	NM_001256790.3 linkuse as main transcript	c.1361G>A	p.Arg454Gln	missense_variant	13/48		NP_001243719.1
CACNA1F	XM_011543983.3 linkuse as main transcript	c.1361G>A	p.Arg454Gln	missense_variant	13/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1F	ENST00000323022.10 linkuse as main transcript	c.1523G>A	p.Arg508Gln	missense_variant	13/48	1	NM_001256789.3	ENSP00000321618		O60840-2
CACNA1F	ENST00000376265.2 linkuse as main transcript	c.1556G>A	p.Arg519Gln	missense_variant	13/48	1		ENSP00000365441	P1	O60840-1
CACNA1F	ENST00000376251.5 linkuse as main transcript	c.1361G>A	p.Arg454Gln	missense_variant	13/48	1		ENSP00000365427		O60840-4

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

1939

AN:

110895

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

577

AN XY:

33207

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.187

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.00152

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0321

Gnomad MID

AF:

0.0212

Gnomad NFE

AF:

0.0262

Gnomad OTH

AF:

0.0108

GnomAD3 exomes

AF:

0.0174

AC:

2498

AN:

143850

Hom.:

AF XY:

0.0183

AC XY:

809

AN XY:

44266

show subpopulations

Gnomad AFR exome

AF:

0.00354

Gnomad AMR exome

AF:

0.00421

Gnomad ASJ exome

AF:

0.00323

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0197

Gnomad FIN exome

AF:

0.0342

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0239

AC:

25796

AN:

1077547

Hom.:

230

Cov.:

AF XY:

0.0240

AC XY:

8440

AN XY:

351193

show subpopulations

Gnomad4 AFR exome

AF:

0.00286

Gnomad4 AMR exome

AF:

0.00399

Gnomad4 ASJ exome

AF:

0.00242

Gnomad4 EAS exome

AF:

0.0000689

Gnomad4 SAS exome

AF:

0.0211

Gnomad4 FIN exome

AF:

0.0362

Gnomad4 NFE exome

AF:

0.0266

Gnomad4 OTH exome

AF:

0.0194

GnomAD4 genome

AF:

0.0174

AC:

1935

AN:

110942

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

576

AN XY:

33266

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.00713

Gnomad4 ASJ

AF:

0.00152

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0221

Gnomad4 FIN

AF:

0.0321

Gnomad4 NFE

AF:

0.0262

Gnomad4 OTH

AF:

0.0100

Alfa

AF:

0.0223

Hom.:

1162

Bravo

AF:

0.0158

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0267

AC:

ESP6500AA

AF:

0.00314

AC:

ESP6500EA

AF:

0.0250

AC:

168

ExAC

AF:

0.0158

AC:

1884

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 180/10956=1.64% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2017	- -

Congenital stationary night blindness 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

.;.;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.1

.;.;M

MutationTaster

Benign

0.013

P;P;P

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.048

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.69

MPC

0.91

ClinPred

0.029

GERP RS

3.6

Varity_R

0.50

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over