Variant rs2184953 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002016.2(FLG):c.6580T>C(p.Tyr2194His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,226 control chromosomes in the GnomAD database, including 63,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.37 ( 14590 hom., cov: 32)

Exomes 𝑓: 0.22 ( 49249 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -5.55

Variant links:

Genes affected

FLG (HGNC:3748): (filaggrin) The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.[provided by RefSeq, Dec 2009]

FLG links:

FLG-AS1 (HGNC:):

FLG-AS1 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=1.5873069E-6).

BP6

Variant 1-152308306-A-G is Benign according to our data. Variant chr1-152308306-A-G is described in ClinVar as [Benign]. Clinvar id is 1244740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152308306-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.6580T>C	p.Tyr2194His	missense_variant	3/3	ENST00000368799.2	NP_002007.1	P20930

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2 linkuse as main transcript	c.6580T>C	p.Tyr2194His	missense_variant	3/3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

55897

AN:

151236

Hom.:

14547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.701

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.422

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.352

GnomAD3 exomes

AF:

0.319

AC:

80243

AN:

251412

Hom.:

17318

AF XY:

0.308

AC XY:

41832

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.717

Gnomad AMR exome

AF:

0.476

Gnomad ASJ exome

AF:

0.314

Gnomad EAS exome

AF:

0.605

Gnomad SAS exome

AF:

0.429

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.219

AC:

320538

AN:

1461870

Hom.:

49249

Cov.:

123

AF XY:

0.222

AC XY:

161774

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.715

Gnomad4 AMR exome

AF:

0.470

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.620

Gnomad4 SAS exome

AF:

0.418

Gnomad4 FIN exome

AF:

0.177

Gnomad4 NFE exome

AF:

0.161

Gnomad4 OTH exome

AF:

0.278

GnomAD4 genome

AF:

0.370

AC:

55989

AN:

151356

Hom.:

14590

Cov.:

AF XY:

0.376

AC XY:

27816

AN XY:

73884

show subpopulations

Gnomad4 AFR

AF:

0.702

Gnomad4 AMR

AF:

0.423

Gnomad4 ASJ

AF:

0.323

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.452

Gnomad4 FIN

AF:

0.193

Gnomad4 NFE

AF:

0.163

Gnomad4 OTH

AF:

0.347

Alfa

AF:

0.230

Hom.:

6418

Bravo

AF:

0.400

TwinsUK

AF:

0.161

AC:

598

ALSPAC

AF:

0.165

AC:

635

ExAC

AF:

0.317

AC:

38520

EpiCase

AF:

0.179

EpiControl

AF:

0.176

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ichthyosis vulgaris

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.097

DANN

Benign

0.33

DEOGEN2

Benign

0.021

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.24

PROVEAN

Benign

0.59

REVEL

Benign

0.0070

Sift

Benign

0.48

Polyphen

0.0030

Vest4

0.046

ClinPred

0.0026

GERP RS

-6.0

Varity_R

0.031

gMVP

0.034

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