rs12568784

chr1-152350656-G-Achr1-152350656-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001014342.3(FLG2):c.7130C>T(p.Ser2377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.322

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]

FLG-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05189991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG2	NM_001014342.3	c.7130C>T	p.Ser2377Leu	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1	n.1406+9446G>A		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1	n.151+9446G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5	c.7130C>T	p.Ser2377Leu	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1	n.757+12567G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.27
Dann	Benign	0.25
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.29		Loss of phosphorylation at S2377 (P = 0.0346);
MVP		0.10
MPC		0.050
ClinPred		0.025	T
GERP RS		0.13
Varity_R		0.028
gMVP		0.021

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

Other links and lift over

dbSNP: rs12568784; hg19: chr1-152323132;