Variant chr1-152351166-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001014342.3(FLG2):c.6620G>C(p.Arg2207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FLG2
NM_001014342.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.74

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.106102765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FLG2	NM_001014342.3 linkuse as main transcript	c.6620G>C	p.Arg2207Pro	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1 linkuse as main transcript	n.1406+9956C>G		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1 linkuse as main transcript	n.151+9956C>G		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.6620G>C	p.Arg2207Pro	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.757+13077C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 02, 2023

The c.6620G>C (p.R2207P) alteration is located in exon 3 (coding exon 2) of the FLG2 gene. This alteration results from a G to C substitution at nucleotide position 6620, causing the arginine (R) at amino acid position 2207 to be replaced by a proline (P). 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

0.27

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.7

DANN

Benign

0.94

DEOGEN2

Benign

0.0057

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.33

M_CAP

Benign

0.0039

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

PrimateAI

Benign

0.17

PROVEAN

Benign

-1.2

REVEL

Benign

0.097

Sift

Benign

0.38

Sift4G

Benign

0.27

Polyphen

0.98

Vest4

0.13

MutPred

0.26

Loss of MoRF binding (P = 4e-04);

MVP

0.095

MPC

0.19

ClinPred

0.45

GERP RS

-7.6

Varity_R

0.090

gMVP

0.039

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over