rs16833974

chr1-152354040-T-C

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.3746A>G(p.His1249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,062 control chromosomes in the GnomAD database, including 1,573 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.057 (852 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (721 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.206

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=0.0045773685).
• BP6: Variant 1-152354040-T-C is Benign according to our data. Variant chr1-152354040-T-C is described in ClinVar as [Benign]. Clinvar id is 1247512.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG2	NM_001014342.3	c.3746A>G	p.His1249Arg	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1	n.1407-9947T>C		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1	n.152-9947T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5	c.3746A>G	p.His1249Arg	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1	n.757+15951T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8715 AN: 152150 Hom.: 851 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0162 AC: 4078 AN: 251318 Hom.: 330 AF XY: 0.0123 AC XY: 1664 AN XY: 135824

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00692 AC: 10114 AN: 1461794 Hom.: 721 Cov.: 37 AF XY: 0.00600 AC XY: 4360 AN XY: 727210

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0574 AC: 8739 AN: 152268 Hom.: 852 Cov.: 33 AF XY: 0.0560 AC XY: 4170 AN XY: 74464

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.0493

Alfa AF: 0.0285 Hom.: 282

Bravo AF: 0.0641

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.191 AC: 842

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.0196 AC: 2373

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00302

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 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.6
Dann	Benign	0.70
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.070
Sift	Benign	0.072	T
Sift4G	Benign	0.092	T
Polyphen		0.68	P
Vest4		0.089
MPC		0.028
ClinPred		0.023	T
GERP RS		2.5
Varity_R		0.10
gMVP		0.015

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: rs16833974; hg19: chr1-152326516; COSMIC: COSV104428670;