Genetic Variant NM_001014342.3:c.6350T>G (chr1-152351436-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001014342.3(FLG2):c.6350T>G(p.Val2117Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2117A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000038 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FLG2
NM_001014342.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.81

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040198088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG2	NM_001014342.3 link	c.6350T>G	p.Val2117Gly	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.6350T>G	p.Val2117Gly	missense_variant	Exon 3 of 3	5	NM_001014342.3	ENSP00000373370.4		Q5D862

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

131830

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000867

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000237

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1459766

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000379

AC:

AN:

131968

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

64842

show subpopulations

Gnomad4 AFR

AF:

0.0000865

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000237

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000107

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0090

DANN

Benign

0.51

DEOGEN2

Benign

0.0038

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.092

M_CAP

Benign

0.0016

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.79

REVEL

Benign

0.027

Sift

Benign

0.48

Sift4G

Benign

0.43

Polyphen

0.025

Vest4

0.17

MVP

0.061

MPC

0.032

ClinPred

0.072

GERP RS

-9.1

Varity_R

0.049

gMVP

0.044

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over