1-152350700-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001014342.3(FLG2):c.7086G>A(p.Gly2362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,614,190 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: FLG2 NM_001014342.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.605

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-152350700-C-T is Benign according to our data. Variant chr1-152350700-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2672355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.605 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG2	NM_001014342.3	c.7086G>A	p.Gly2362=	synonymous_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1	n.1406+9490C>T		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1	n.151+9490C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5	c.7086G>A	p.Gly2362=	synonymous_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1	n.757+12611C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000807 AC: 203 AN: 251430 Hom.: 0 AF XY: 0.000581 AC XY: 79 AN XY: 135886

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000373 AC: 545 AN: 1461888 Hom.: 3 Cov.: 36 AF XY: 0.000331 AC XY: 241 AN XY: 727242

Gnomad4 AFR exome AF: 0.00989

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74474

Gnomad4 AFR AF: 0.00876

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00293

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

FLG2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	1.5
Dann	Benign	0.55

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: rs139767736; hg19: chr1-152323176;