NM_002016.2:c.2938C>G

Variant names:

Variant summary

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

The NM_002016.2(FLG):c.2938C>G(p.His980Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,577,942 control chromosomes in the GnomAD database, including 708 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 (★★).

Frequency

Genomes: 𝑓 0.025 ( 52 hom., cov: 30)

Exomes 𝑓: 0.026 ( 656 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.19

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023139417).

BP6

Variant 1-152311948-G-C is Benign according to our data. Variant chr1-152311948-G-C is described in ClinVar as [Benign]. Clinvar id is 402869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152311948-G-C is described in Lovd as [Likely_benign]. Variant chr1-152311948-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2 link	c.2938C>G	p.His980Asp	missense_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.2938C>G	p.His980Asp	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3449

AN:

137672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0224

Gnomad EAS

AF:

0.0288

Gnomad SAS

AF:

0.0709

Gnomad FIN

AF:

0.00891

Gnomad MID

AF:

0.0417

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0236

AC:

5885

AN:

249840

Hom.:

106

AF XY:

0.0255

AC XY:

3454

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.0190

Gnomad SAS exome

AF:

0.0565

Gnomad FIN exome

AF:

0.00836

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0233

GnomAD4 exome

AF:

0.0255

AC:

36725

AN:

1440190

Hom.:

656

Cov.:

114

AF XY:

0.0266

AC XY:

19040

AN XY:

716578

show subpopulations

Gnomad4 AFR exome

AF:

0.0277

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.0227

Gnomad4 EAS exome

AF:

0.0467

Gnomad4 SAS exome

AF:

0.0586

Gnomad4 FIN exome

AF:

0.00927

Gnomad4 NFE exome

AF:

0.0236

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0250

AC:

3447

AN:

137752

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1709

AN XY:

67010

show subpopulations

Gnomad4 AFR

AF:

0.0261

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.0224

Gnomad4 EAS

AF:

0.0288

Gnomad4 SAS

AF:

0.0713

Gnomad4 FIN

AF:

0.00891

Gnomad4 NFE

AF:

0.0240

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0126

Hom.:

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0259

AC:

100

ExAC

AF:

0.0255

AC:

3094

EpiCase

AF:

0.0234

EpiControl

AF:

0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: 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: Gene associated with ichthyosis/dermatitis -

Ichthyosis vulgaris

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0020

DANN

Benign

0.47

DEOGEN2

Benign

0.026

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.00029

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

REVEL

Benign

0.023

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.022

ClinPred

0.0033

GERP RS

-6.6

Varity_R

0.034

gMVP

0.0099

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