Genetic Variant NM_001014342.3:c.7130C>A (chr1-152350656-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001014342.3(FLG2):c.7130C>A(p.Ser2377*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,613,920 control chromosomes in the GnomAD database, including 31,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4166 hom., cov: 32)

Exomes 𝑓: 0.18 ( 27054 hom. )

Consequence

FLG2
NM_001014342.3 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.322

Publications

45 publications found

Variant links:

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]

FLG2 links:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00641 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 1-152350656-G-T is Benign according to our data. Variant chr1-152350656-G-T is described in ClinVar as Benign. ClinVar VariationId is 1287657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG2	NM_001014342.3 link	c.7130C>A	p.Ser2377*	stop_gained	Exon 3 of 3	ENST00000388718.5	NP_001014364.1	Q5D862

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG2	ENST00000388718.5 link	c.7130C>A	p.Ser2377*	stop_gained	Exon 3 of 3	5	NM_001014342.3	ENSP00000373370.4		Q5D862

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32856

AN:

151956

Hom.:

4159

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.236

AC:

59311

AN:

251198

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.285

Gnomad EAS exome

AF:

0.461

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.158

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.178

AC:

260367

AN:

1461846

Hom.:

27054

Cov.:

AF XY:

0.180

AC XY:

130810

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.267

AC:

8933

AN:

33480

American (AMR)

AF:

0.364

AC:

16257

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

7445

AN:

26136

East Asian (EAS)

AF:

0.441

AC:

17510

AN:

39700

South Asian (SAS)

AF:

0.280

AC:

24188

AN:

86250

European-Finnish (FIN)

AF:

0.136

AC:

7260

AN:

53418

Middle Eastern (MID)

AF:

0.259

AC:

1491

AN:

5766

European-Non Finnish (NFE)

AF:

0.148

AC:

164686

AN:

1111986

Other (OTH)

AF:

0.209

AC:

12597

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

13415

26831

40246

53662

67077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6290

12580

18870

25160

31450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.216

AC:

32882

AN:

152074

Hom.:

4166

Cov.:

AF XY:

0.222

AC XY:

16506

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.265

AC:

10983

AN:

41440

American (AMR)

AF:

0.315

AC:

4812

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1035

AN:

3464

East Asian (EAS)

AF:

0.449

AC:

2325

AN:

5176

South Asian (SAS)

AF:

0.295

AC:

1422

AN:

4816

European-Finnish (FIN)

AF:

0.139

AC:

1469

AN:

10584

Middle Eastern (MID)

AF:

0.267

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.148

AC:

10084

AN:

67992

Other (OTH)

AF:

0.234

AC:

495

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1273

2547

3820

5094

6367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.192

Hom.:

6691

Bravo

AF:

0.233

TwinsUK

AF:

0.144

AC:

534

ALSPAC

AF:

0.150

AC:

580

ESP6500AA

AF:

0.261

AC:

1148

ESP6500EA

AF:

0.159

AC:

1368

ExAC

AF:

0.232

AC:

28174

Asia WGS

AF:

0.363

AC:

1261

AN:

3478

EpiCase

AF:

0.164

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24176758, 24608987, 24184149) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

-0.093

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.041

PhyloP100

0.32

Vest4

0.045

GERP RS

0.13

Mutation Taster

=188/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over