rs781923856

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The NM_001256789.3(CACNA1F):c.1606G>A(p.Ala536Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,056,120 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A536A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 4 hem. )

Consequence

CACNA1F
NM_001256789.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.96

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Aland island eye disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
inherited retinal dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
congenital stationary night blindness 2A
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
X-linked cone-rod dystrophy 3
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1F links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP5

Variant X-49225954-C-T is Pathogenic according to our data. Variant chrX-49225954-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520685.

BS2

High AC in GnomAdExome4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1F	NM_001256789.3 link	c.1606G>A	p.Ala536Thr	missense_variant	Exon 13 of 48	ENST00000323022.10	NP_001243718.1	O60840-2
CACNA1F	NM_005183.4 link	c.1639G>A	p.Ala547Thr	missense_variant	Exon 13 of 48		NP_005174.2	O60840-1
CACNA1F	NM_001256790.3 link	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 48		NP_001243719.1	O60840-4
CACNA1F	XM_011543983.3 link	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 47		XP_011542285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1F	ENST00000323022.10 link	c.1606G>A	p.Ala536Thr	missense_variant	Exon 13 of 48	1	NM_001256789.3	ENSP00000321618.6	O60840-2
CACNA1F	ENST00000376265.2 link	c.1639G>A	p.Ala547Thr	missense_variant	Exon 13 of 48	1		ENSP00000365441.2	O60840-1
CACNA1F	ENST00000376251.5 link	c.1444G>A	p.Ala482Thr	missense_variant	Exon 13 of 48	1		ENSP00000365427.1	O60840-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

117830

AF XY:

0.0000244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000217

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1056120

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

345238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25062

American (AMR)

AF:

0.00

AC:

AN:

28185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18665

East Asian (EAS)

AF:

0.00

AC:

AN:

27332

South Asian (SAS)

AF:

0.000120

AC:

AN:

49994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37791

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.00000609

AC:

AN:

820541

Other (OTH)

AF:

0.00

AC:

AN:

44462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000194

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

May 20, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1F protein function. ClinVar contains an entry for this variant (Variation ID: 520685). This variant has not been reported in the literature in individuals affected with CACNA1F-related conditions. This variant is present in population databases (rs781923856, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 547 of the CACNA1F protein (p.Ala547Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.80

.;.;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;.;M

PhyloP100

5.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.10

T;T;T

Sift4G

Uncertain

0.057

T;T;T

Polyphen

1.0

.;.;D

Vest4

0.64

MutPred

0.51

.;.;Gain of disorder (P = 0.1043);

MVP

0.97

MPC

0.64

ClinPred

0.81

GERP RS

3.6

Varity_R

0.34

gMVP

0.83

Mutation Taster

=92/8

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over