rs141010716

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V624D) has been classified as Uncertain significance.

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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 21. This position FAILED quality control check.

BS2

High Hemizygotes in GnomAd4 at 63 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3 link	c.1870G>A	p.Val624Ile	missense_variant	Exon 14 of 48	ENST00000323022.10	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4 link	c.1903G>A	p.Val635Ile	missense_variant	Exon 14 of 48		NP_005174.2	O60840-1
CACNA1F	NM_001256790.3 link	c.1708G>A	p.Val570Ile	missense_variant	Exon 14 of 48		NP_001243719.1	O60840-4
CACNA1F	XM_011543983.3 link	c.1708G>A	p.Val570Ile	missense_variant	Exon 14 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1F	ENST00000323022.10 link	c.1870G>A	p.Val624Ile	missense_variant	Exon 14 of 48	1	NM_001256789.3	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2 link	c.1903G>A	p.Val635Ile	missense_variant	Exon 14 of 48	1		ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5 link	c.1708G>A	p.Val570Ile	missense_variant	Exon 14 of 48	1		ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

252

AN:

110862

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00206

AC:

265

AN:

128537

AF XY:

0.00199

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 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

AC:

AN:

25041

Gnomad4 AMR exome

AF:

0.000817

AC:

AN:

29383

Gnomad4 ASJ exome

AF:

0.000214

AC:

AN:

18659

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

27866

Gnomad4 SAS exome

AF:

0.000179

AC:

AN:

50184

Gnomad4 FIN exome

AF:

0.00117

AC:

AN:

38384

Gnomad4 NFE exome

AF:

0.00389

AC:

3155

AN:

811778

Gnomad4 Remaining exome

AF:

0.00320

AC:

142

AN:

44387

Heterozygous variant carriers

110

221

331

442

552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.000722116

AN:

0.000722116

Gnomad4 AMR

AF:

0.000762

AC:

0.000761832

AN:

0.000761832

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000389

AC:

0.0003885

AN:

0.0003885

Gnomad4 FIN

AF:

0.000336

AC:

0.000335965

AN:

0.000335965

Gnomad4 NFE

AF:

0.00405

AC:

0.00404705

AN:

0.00404705

Gnomad4 OTH

AF:

0.00199

AC:

0.00198939

AN:

0.00198939

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00263

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

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

not provided

Uncertain:1Benign:2

Nov 29, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital stationary night blindness 2A

Benign:1

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Jan 01, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Mutation Taster

=100/0

polymorphism (auto)

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