chr5-148101392-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006846.4(SPINK5):c.1258A>G(p.Lys420Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,604,162 control chromosomes in the GnomAD database, including 212,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16463 hom., cov: 30)

Exomes 𝑓: 0.51 ( 196506 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.253

Publications

83 publications found

Variant links:

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SPINK5 links:

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

FBXO38-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.7063567E-6).

BP6

Variant 5-148101392-A-G is Benign according to our data. Variant chr5-148101392-A-G is described in ClinVar as Benign. ClinVar VariationId is 5269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	NM_006846.4	MANE Select	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 33	NP_006837.2	Q9NQ38-1
SPINK5	NM_001127698.2		c.1258A>G	p.Lys420Glu	missense	Exon 14 of 34	NP_001121170.1	Q9NQ38-3
SPINK5	NM_001127699.2		c.1258A>G	p.Lys420Glu	missense	Exon 14 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 33	ENSP00000256084.7	Q9NQ38-1
SPINK5	ENST00000359874.7	TSL:1	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 34	ENSP00000352936.3	Q9NQ38-3
SPINK5	ENST00000398454.5	TSL:1	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67772

AN:

151496

Hom.:

16453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.524

Gnomad OTH

AF:

0.475

GnomAD2 exomes

AF:

0.521

AC:

129392

AN:

248520

AF XY:

0.519

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.700

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.524

GnomAD4 exome

AF:

0.515

AC:

747723

AN:

1452548

Hom.:

196506

Cov.:

AF XY:

0.514

AC XY:

371420

AN XY:

722976

show subpopulations

African (AFR)

AF:

0.228

AC:

7616

AN:

33348

American (AMR)

AF:

0.685

AC:

30561

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12016

AN:

26052

East Asian (EAS)

AF:

0.447

AC:

17688

AN:

39606

South Asian (SAS)

AF:

0.489

AC:

42067

AN:

86050

European-Finnish (FIN)

AF:

0.550

AC:

29342

AN:

53374

Middle Eastern (MID)

AF:

0.508

AC:

2917

AN:

5740

European-Non Finnish (NFE)

AF:

0.521

AC:

575364

AN:

1103656

Other (OTH)

AF:

0.502

AC:

30152

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

18141

36282

54423

72564

90705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16410

32820

49230

65640

82050

<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:

0.447

AC:

67794

AN:

151614

Hom.:

16463

Cov.:

AF XY:

0.451

AC XY:

33372

AN XY:

74020

show subpopulations

African (AFR)

AF:

0.237

AC:

9810

AN:

41358

American (AMR)

AF:

0.581

AC:

8836

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

1577

AN:

3470

East Asian (EAS)

AF:

0.476

AC:

2426

AN:

5100

South Asian (SAS)

AF:

0.491

AC:

2357

AN:

4802

European-Finnish (FIN)

AF:

0.535

AC:

5600

AN:

10462

Middle Eastern (MID)

AF:

0.493

AC:

143

AN:

290

European-Non Finnish (NFE)

AF:

0.524

AC:

35577

AN:

67902

Other (OTH)

AF:

0.477

AC:

1005

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1773

3546

5319

7092

8865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

632

1264

1896

2528

3160

<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:

0.498

Hom.:

61124

Bravo

AF:

0.445

TwinsUK

AF:

0.530

AC:

1964

ALSPAC

AF:

0.528

AC:

2035

ESP6500AA

AF:

0.256

AC:

946

ESP6500EA

AF:

0.513

AC:

4204

ExAC

AF:

0.507

AC:

61268

Asia WGS

AF:

0.520

AC:

1802

AN:

3478

EpiCase

AF:

0.518

EpiControl

AF:

0.531

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Netherton syndrome (2)

Ichthyosis linearis circumflexa (1)

not provided (2)

SPINK5 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.1

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.026

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00099

LIST_S2

Benign

0.058

MetaRNN

Benign

0.0000057

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.81

PhyloP100

0.25

PrimateAI

Benign

0.39

PROVEAN

Benign

1.0

REVEL

Benign

0.038

Sift

Benign

0.95

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.049

MPC

0.13

ClinPred

0.0073

GERP RS

2.8

Varity_R

0.086

gMVP

0.28

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over