Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001014342.3(FLG2):c.3746A>G(p.His1249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,062 control chromosomes in the GnomAD database, including 1,573 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 852 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 721 hom. )

Consequence

FLG2
NM_001014342.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.206

Publications

12 publications found

Variant links:

Genes affected

FLG2 (HGNC:33276): (filaggrin 2) The filaggrin-like protein encoded by this gene is upregulated by calcium, proteolyzed by calpain 1, and is involved in epithelial homeostasis. The encoded protein is required for proper cornification in skin, with defects in this gene being associated with skin diseases. This protein also has a function in skin barrier protection. In fact, in addition to providing a physical barrier, C-terminal fragments of this protein display antimicrobial activity against P. aeruginosa and E. coli. [provided by RefSeq, Jul 2020]

FLG2 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=0.0045773685).

BP6

Variant 1-152354040-T-C is Benign according to our data. Variant chr1-152354040-T-C is described in ClinVar as Benign. ClinVar VariationId is 1247512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014342.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLG2	NM_001014342.3	MANE Select	c.3746A>G	p.His1249Arg	missense	Exon 3 of 3	NP_001014364.1
CCDST	NR_103778.1		n.1407-9947T>C		intron	N/A
CCDST	NR_103779.1		n.152-9947T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLG2	ENST00000388718.5	TSL:5 MANE Select	c.3746A>G	p.His1249Arg	missense	Exon 3 of 3	ENSP00000373370.4
CCDST	ENST00000445097.2	TSL:1	n.152-9947T>C		intron	N/A
CCDST	ENST00000392688.7	TSL:2	n.1407-9947T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0573

AC:

8715

AN:

152150

Hom.:

851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.0498

GnomAD2 exomes

AF:

0.0162

AC:

4078

AN:

251318

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.203

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.00692

AC:

10114

AN:

1461794

Hom.:

721

Cov.:

AF XY:

0.00600

AC XY:

4360

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.202

AC:

6749

AN:

33478

American (AMR)

AF:

0.0136

AC:

609

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

128

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000603

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00144

AC:

1596

AN:

1111922

Other (OTH)

AF:

0.0146

AC:

882

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

590

1181

1771

2362

2952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<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:

0.0574

AC:

8739

AN:

152268

Hom.:

852

Cov.:

AF XY:

0.0560

AC XY:

4170

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.196

AC:

8144

AN:

41532

American (AMR)

AF:

0.0222

AC:

339

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00184

AC:

125

AN:

68026

Other (OTH)

AF:

0.0493

AC:

104

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

360

719

1079

1438

1798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0287

Hom.:

412

Bravo

AF:

0.0641

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.191

AC:

842

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.0196

AC:

2373

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00302

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.6

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.024

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.21

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.070

Sift

Benign

0.072

Sift4G

Benign

0.092

Polyphen

0.68

Vest4

0.089

MPC

0.028

ClinPred

0.023

GERP RS

2.5

Varity_R

0.10

gMVP

0.015

Mutation Taster

=99/1

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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rs16833974

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over