1-152351623-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001014342.3(FLG2):c.6163G>A(p.Gly2055Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,583,208 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0071 (46 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (599 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.899

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023601651).
• BP6: Variant 1-152351623-C-T is Benign according to our data. Variant chr1-152351623-C-T is described in ClinVar as [Benign]. Clinvar id is 1261755.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG2	NM_001014342.3	c.6163G>A	p.Gly2055Arg	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1	n.1406+10413C>T		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1	n.151+10413C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5	c.6163G>A	p.Gly2055Arg	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1	n.757+13534C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 879 AN: 123734 Hom.: 46 Cov.: 30

Gnomad AFR AF: 0.000282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000564

Gnomad ASJ AF: 0.000661

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000729

Gnomad OTH AF: 0.00462

GnomAD3 exomes AF: 0.0113 AC: 2710 AN: 239940 Hom.: 150 AF XY: 0.0104 AC XY: 1354 AN XY: 130090

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.000406

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00980

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.00665

GnomAD4 exome AF: 0.00555 AC: 8105 AN: 1459384 Hom.: 599 Cov.: 37 AF XY: 0.00549 AC XY: 3986 AN XY: 726016

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.000250

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00541

GnomAD4 genome AF: 0.00708 AC: 877 AN: 123824 Hom.: 46 Cov.: 30 AF XY: 0.00848 AC XY: 516 AN XY: 60838

Gnomad4 AFR AF: 0.000281

Gnomad4 AMR AF: 0.000563

Gnomad4 ASJ AF: 0.000661

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.00615

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.000729

Gnomad4 OTH AF: 0.00403

Alfa AF: 0.00147 Hom.: 0

ExAC AF: 0.0113 AC: 1367

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Benign	0.037	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.11
MutPred		0.35		Gain of sheet (P = 0.0221);
MPC		0.22
ClinPred		0.033	T
GERP RS		3.8
Varity_R		0.056
gMVP		0.020

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: rs77345168; hg19: chr1-152324099; COSMIC: COSV66167325;