Variant 1-152350951-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001014342.3(FLG2):c.6835G>A(p.Ala2279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,888 control chromosomes in the GnomAD database, including 5 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 5 hom. )

Consequence

FLG2
NM_001014342.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.37

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:27913): (cervical cancer associated DHX9 suppressive transcript)

FLG-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010793209).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FLG2	NM_001014342.3 linkuse as main transcript	c.6835G>A	p.Ala2279Thr	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1 linkuse as main transcript	n.1406+9741C>T		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1 linkuse as main transcript	n.151+9741C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5 linkuse as main transcript	c.6835G>A	p.Ala2279Thr	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.757+12862C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000856

AC:

130

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000899

AC:

226

AN:

251434

Hom.:

AF XY:

0.000809

AC XY:

110

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00138

AC:

2022

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

983

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000855

AC:

130

AN:

152038

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.00180

EpiControl

AF:

0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.6835G>A (p.A2279T) alteration is located in exon 3 (coding exon 2) of the FLG2 gene. This alteration results from a G to A substitution at nucleotide position 6835, causing the alanine (A) at amino acid position 2279 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.13

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0037

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.35

M_CAP

Benign

0.0014

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.47

REVEL

Benign

0.049

Sift

Benign

0.28

Sift4G

Benign

1.0

Polyphen

1.0

Vest4

0.062

MVP

0.13

MPC

0.052

ClinPred

0.034

GERP RS

-3.2

Varity_R

0.027

gMVP

0.024

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