chr17-81528536-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_012418.4(FSCN2):c.5C>T(p.Pro2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000535 in 1,590,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

FSCN2
NM_012418.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.97

Variant links:

Genes affected

FSCN2 (HGNC:3960): (fascin actin-bundling protein 2, retinal) This gene encodes a member of the fascin protein family. Fascins crosslink actin into filamentous bundles within dynamic cell extensions. This family member is proposed to play a role in photoreceptor disk morphogenesis. A mutation in this gene results in one form of autosomal dominant retinitis pigmentosa and macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

FSCN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.371544).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FSCN2	NM_012418.4 link	c.5C>T	p.Pro2Leu	missense_variant	Exon 1 of 5	ENST00000417245.7	NP_036550.1	O14926-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FSCN2	ENST00000417245.7 link	c.5C>T	p.Pro2Leu	missense_variant	Exon 1 of 5	1	NM_012418.4	ENSP00000388716.2		O14926-1
FSCN2	ENST00000334850.7 link	c.5C>T	p.Pro2Leu	missense_variant	Exon 1 of 5	5		ENSP00000334665.7		O14926-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000881

AC:

AN:

215696

Hom.:

AF XY:

0.0000340

AC XY:

AN XY:

117674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000446

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000738

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000316

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000543

AC:

AN:

1437742

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

712710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000912

Gnomad4 AMR exome

AF:

0.000310

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.0000601

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000500

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000748

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.P2L) alteration is located in exon 1 (coding exon 1) of the FSCN2 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the proline (P) at amino acid position 2 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2 of the FSCN2 protein (p.Pro2Leu). This variant is present in population databases (rs538029653, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FSCN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1423716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.098

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.49

P;.

Vest4

0.62

MutPred

0.25

Loss of catalytic residue at P2 (P = 0.0045);Loss of catalytic residue at P2 (P = 0.0045);

MVP

0.71

MPC

0.41

ClinPred

0.19

GERP RS

4.2

Varity_R

0.17

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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