rs146849256

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_002016.2(FLG):c.7801G>A(p.Asp2601Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,610,448 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.338

Publications

2 publications found

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:

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

CCDST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008227736).

BP6

Variant 1-152307085-C-T is Benign according to our data. Variant chr1-152307085-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445660.

BS2

High Homozygotes in GnomAdExome4 at 4 SD,XL,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	NM_002016.2	MANE Select	c.7801G>A	p.Asp2601Asn	missense	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-25498C>T		intron	N/A
CCDST	NR_186762.1		n.180-25498C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.7801G>A	p.Asp2601Asn	missense	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.462+5252C>T		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.376+5252C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

166

AN:

148470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000603

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000967

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00211

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.000993

AC:

249

AN:

250844

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00169

AC:

2477

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1190

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33464

American (AMR)

AF:

0.000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00209

AC:

2319

AN:

1112012

Other (OTH)

AF:

0.00147

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

159

318

478

637

796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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

AF:

0.00112

AC:

166

AN:

148586

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

AN XY:

72442

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

39304

American (AMR)

AF:

0.000602

AC:

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

4978

South Asian (SAS)

AF:

0.00

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

10342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00211

AC:

143

AN:

67662

Other (OTH)

AF:

0.00145

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00101

AC:

123

EpiCase

AF:

0.00196

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.0

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.019

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.58

M_CAP

Benign

0.0022

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

PhyloP100

-0.34

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.54

REVEL

Benign

0.086

Sift

Benign

0.047

Polyphen

0.61

Vest4

0.042

MVP

0.12

ClinPred

0.012

GERP RS

-2.3

Varity_R

0.035

gMVP

0.034

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over