Genetic Variant FLG2:p.His1249Arg (chr1-152354040-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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=0.0045773685).

BP6

Variant 1-152354040-T-C is Benign according to our data. Variant chr1-152354040-T-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG2	NM_001014342.3 link	c.3746A>G	p.His1249Arg	missense_variant	Exon 3 of 3	ENST00000388718.5	NP_001014364.1	Q5D862

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG2	ENST00000388718.5 link	c.3746A>G	p.His1249Arg	missense_variant	Exon 3 of 3	5	NM_001014342.3	ENSP00000373370.4		Q5D862

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

GnomAD3 exomes

AF:

0.0162

AC:

4078

AN:

251318

Hom.:

330

AF XY:

0.0123

AC XY:

1664

AN XY:

135824

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 SAS exome

AF:

0.000425

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

Gnomad4 AFR exome

AF:

0.202

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00144

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0574

AC:

8739

AN:

152268

Hom.:

852

Cov.:

AF XY:

0.0560

AC XY:

4170

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.0222

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.0493

Alfa

AF:

0.0285

Hom.:

282

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

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

0.18

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.6

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

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

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