rs12756586

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

17 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: Benign. The variant received -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 VariationId is 402869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

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.2938C>G	p.His980Asp	missense	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-20635G>C		intron	N/A
CCDST	NR_186762.1		n.180-20635G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.2938C>G	p.His980Asp	missense	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.463-2958G>C		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.377-2958G>C		intron	N/A

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

GnomAD2 exomes

AF:

0.0236

AC:

5885

AN:

249840

AF XY:

0.0255

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 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

African (AFR)

AF:

0.0277

AC:

697

AN:

25158

American (AMR)

AF:

0.0142

AC:

618

AN:

43438

Ashkenazi Jewish (ASJ)

AF:

0.0227

AC:

585

AN:

25718

East Asian (EAS)

AF:

0.0467

AC:

1821

AN:

38984

South Asian (SAS)

AF:

0.0586

AC:

4777

AN:

81550

European-Finnish (FIN)

AF:

0.00927

AC:

491

AN:

52986

Middle Eastern (MID)

AF:

0.0376

AC:

200

AN:

5318

European-Non Finnish (NFE)

AF:

0.0236

AC:

26117

AN:

1108110

Other (OTH)

AF:

0.0241

AC:

1419

AN:

58928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

3093

6186

9279

12372

15465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1028

2056

3084

4112

5140

<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:

0.0250

AC:

3447

AN:

137752

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1709

AN XY:

67010

show subpopulations

African (AFR)

AF:

0.0261

AC:

845

AN:

32372

American (AMR)

AF:

0.0230

AC:

321

AN:

13944

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

AN:

3262

East Asian (EAS)

AF:

0.0288

AC:

129

AN:

4476

South Asian (SAS)

AF:

0.0713

AC:

305

AN:

4278

European-Finnish (FIN)

AF:

0.00891

AC:

AN:

10102

Middle Eastern (MID)

AF:

0.0414

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0240

AC:

1588

AN:

66188

Other (OTH)

AF:

0.0241

AC:

AN:

1952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0126

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Ichthyosis vulgaris (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0020

(source)

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

PhyloP100

-3.2

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

Mutation Taster

=100/0

polymorphism (auto)

(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

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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