1-152351526-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001014342.3(FLG2):c.6260A>G(p.His2087Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0064 in 1,612,708 control chromosomes in the GnomAD database, including 77 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 0.0043 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0066 (73 hom.)
• Consequence: FLG2 NM_001014342.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.107

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=0.00496462).
• BP6: Variant 1-152351526-T-C is Benign according to our data. Variant chr1-152351526-T-C is described in ClinVar as [Benign]. Clinvar id is 2639331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00662 (9679/1461594) while in subpopulation MID AF= 0.0319 (184/5766). AF 95% confidence interval is 0.0281. There are 73 homozygotes in gnomad4_exome. There are 5325 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG2	NM_001014342.3	c.6260A>G	p.His2087Arg	missense_variant	3/3	ENST00000388718.5
FLG-AS1	NR_103778.1	n.1406+10316T>C		intron_variant, non_coding_transcript_variant
FLG-AS1	NR_103779.1	n.151+10316T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG2	ENST00000388718.5	c.6260A>G	p.His2087Arg	missense_variant	3/3	5	NM_001014342.3	P1
FLG-AS1	ENST00000653548.1	n.757+13437T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 654 AN: 151000 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00515

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.000859

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00916

GnomAD3 exomes AF: 0.00671 AC: 1687 AN: 251428 Hom.: 20 AF XY: 0.00780 AC XY: 1060 AN XY: 135872

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00708

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0184

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00662 AC: 9679 AN: 1461594 Hom.: 73 Cov.: 37 AF XY: 0.00732 AC XY: 5325 AN XY: 727088

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0182

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00627

Gnomad4 OTH exome AF: 0.00711

GnomAD4 genome AF: 0.00430 AC: 650 AN: 151114 Hom.: 4 Cov.: 31 AF XY: 0.00387 AC XY: 286 AN XY: 73848

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00515

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.0132

Gnomad4 FIN AF: 0.000859

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.00906

Alfa AF: 0.00587 Hom.: 2

Bravo AF: 0.00475

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00684 AC: 830

EpiCase AF: 0.00769

EpiControl AF: 0.00919

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

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

FLG2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.80
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.024
Sift	Benign	0.064	T
Sift4G	Benign	0.25	T
Polyphen		0.015	B
Vest4		0.20
MVP		0.13
MPC		0.21
ClinPred		0.0024	T
GERP RS		2.3
Varity_R		0.049
gMVP		0.055

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: rs141384852; hg19: chr1-152324002; COSMIC: COSV104428650;