rs141010716

Positions:

chrX-49224768-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001256789.3(CACNA1F):c.1870G>A(p.Val624Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,160,649 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., 63 hem., cov: 21)

Exomes 𝑓: 0.0033 ( 8 hom. 1046 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.448

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011872292).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (252/110916) while in subpopulation NFE AF= 0.00405 (214/52878). AF 95% confidence interval is 0.0036. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 63 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1F	NM_001256789.3 linkuse as main transcript	c.1870G>A	p.Val624Ile	missense_variant	14/48	ENST00000323022.10	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4 linkuse as main transcript	c.1903G>A	p.Val635Ile	missense_variant	14/48		NP_005174.2	O60840-1
CACNA1F	NM_001256790.3 linkuse as main transcript	c.1708G>A	p.Val570Ile	missense_variant	14/48		NP_001243719.1	O60840-4
CACNA1F	XM_011543983.3 linkuse as main transcript	c.1708G>A	p.Val570Ile	missense_variant	14/47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1F	ENST00000323022.10 linkuse as main transcript	c.1870G>A	p.Val624Ile	missense_variant	14/48	1	NM_001256789.3	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2 linkuse as main transcript	c.1903G>A	p.Val635Ile	missense_variant	14/48	1		ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5 linkuse as main transcript	c.1708G>A	p.Val570Ile	missense_variant	14/48	1		ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

252

AN:

110862

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

AN XY:

33088

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000763

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000387

Gnomad FIN

AF:

0.000336

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00405

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00206

AC:

265

AN:

128537

Hom.:

AF XY:

0.00199

AC XY:

AN XY:

41733

show subpopulations

Gnomad AFR exome

AF:

0.000709

Gnomad AMR exome

AF:

0.000999

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.000641

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00326

AC:

3421

AN:

1049733

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

1046

AN XY:

334273

show subpopulations

Gnomad4 AFR exome

AF:

0.000679

Gnomad4 AMR exome

AF:

0.000817

Gnomad4 ASJ exome

AF:

0.000214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000179

Gnomad4 FIN exome

AF:

0.00117

Gnomad4 NFE exome

AF:

0.00389

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.00227

AC:

252

AN:

110916

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

AN XY:

33152

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000762

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000389

Gnomad4 FIN

AF:

0.000336

Gnomad4 NFE

AF:

0.00405

Gnomad4 OTH

AF:

0.00199

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.00202

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00329

AC:

ExAC

AF:

0.00169

AC:

193

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

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: Variant has been reported in unknown number of patients with XL congenital stationary night blindness (Weleber 2002 - from abstract, full text not available). MAF 0.6%, 6 hem in ExAC. Status PASS, but relatively poorly covered (51/9104 Eur chr). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Congenital stationary night blindness 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Retinal dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Uncertain

0.48

.;.;T

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.0

.;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.28

N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.66

.;.;P

Vest4

0.44

MVP

0.82

MPC

0.48

ClinPred

0.021

GERP RS

3.4

Varity_R

0.15

gMVP

0.70

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

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