rs11582620

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002016.2(FLG):c.1236T>C(p.Arg412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,394 control chromosomes in the GnomAD database, including 12,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 912 hom., cov: 31)

Exomes 𝑓: 0.12 ( 11768 hom. )

Consequence

FLG
NM_002016.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.63

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:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-152313650-A-G is Benign according to our data. Variant chr1-152313650-A-G is described in ClinVar as [Benign]. Clinvar id is 1259919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152313650-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.63 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2 link	c.1236T>C	p.Arg412Arg	synonymous_variant	Exon 3 of 3	ENST00000368799.2	NP_002007.1	P20930

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2 link	c.1236T>C	p.Arg412Arg	synonymous_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.0914

AC:

13834

AN:

151386

Hom.:

914

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.144

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0646

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.0871

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.0805

GnomAD3 exomes

AF:

0.116

AC:

29148

AN:

251476

Hom.:

1961

AF XY:

0.122

AC XY:

16594

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0931

Gnomad ASJ exome

AF:

0.0614

Gnomad EAS exome

AF:

0.102

Gnomad SAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.122

AC:

178877

AN:

1461886

Hom.:

11768

Cov.:

AF XY:

0.125

AC XY:

91264

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.0893

Gnomad4 ASJ exome

AF:

0.0656

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.128

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.0913

AC:

13830

AN:

151508

Hom.:

912

Cov.:

AF XY:

0.0932

AC XY:

6893

AN XY:

73998

show subpopulations

Gnomad4 AFR

AF:

0.0213

Gnomad4 AMR

AF:

0.0787

Gnomad4 ASJ

AF:

0.0646

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.124

Gnomad4 OTH

AF:

0.0787

Alfa

AF:

0.111

Hom.:

1627

Bravo

AF:

0.0825

Asia WGS

AF:

0.117

AC:

407

AN:

3478

EpiCase

AF:

0.122

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

FLG-related disorder

Benign:1

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.1

DANN

Benign

0.46

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