5-148120328-G-T

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.2475G>T(p.Glu825Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,603,508 control chromosomes in the GnomAD database, including 11,474 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1130 hom., cov: 31)

Exomes 𝑓: 0.10 ( 10344 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.623

Publications

38 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=0.004297644).

BP6

Variant 5-148120328-G-T is Benign according to our data. Variant chr5-148120328-G-T is described in ClinVar as Benign. ClinVar VariationId is 139262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2475G>T	p.Glu825Asp	missense_variant	Exon 26 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.2475G>T	p.Glu825Asp	missense_variant	Exon 26 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16337

AN:

151894

Hom.:

1131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.0792

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.0873

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.128

GnomAD2 exomes

AF:

0.129

AC:

30151

AN:

233340

AF XY:

0.136

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0630

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.0806

Gnomad NFE exome

AF:

0.0815

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.0997

AC:

144722

AN:

1451500

Hom.:

10344

Cov.:

AF XY:

0.106

AC XY:

76379

AN XY:

720742

show subpopulations

African (AFR)

AF:

0.116

AC:

3856

AN:

33160

American (AMR)

AF:

0.0659

AC:

2882

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4862

AN:

25948

East Asian (EAS)

AF:

0.292

AC:

11450

AN:

39262

South Asian (SAS)

AF:

0.292

AC:

24647

AN:

84400

European-Finnish (FIN)

AF:

0.0851

AC:

4500

AN:

52856

Middle Eastern (MID)

AF:

0.185

AC:

1066

AN:

5756

European-Non Finnish (NFE)

AF:

0.0765

AC:

84605

AN:

1106368

Other (OTH)

AF:

0.114

AC:

6854

AN:

60016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

7684

15367

23051

30734

38418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3410

6820

10230

13640

17050

<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:

0.107

AC:

16326

AN:

152008

Hom.:

1130

Cov.:

AF XY:

0.112

AC XY:

8295

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.113

AC:

4693

AN:

41480

American (AMR)

AF:

0.0791

AC:

1209

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

635

AN:

3468

East Asian (EAS)

AF:

0.309

AC:

1585

AN:

5134

South Asian (SAS)

AF:

0.304

AC:

1458

AN:

4798

European-Finnish (FIN)

AF:

0.0873

AC:

922

AN:

10560

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0803

AC:

5455

AN:

67974

Other (OTH)

AF:

0.129

AC:

273

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

723

1447

2170

2894

3617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.0927

Hom.:

3438

Bravo

AF:

0.104

TwinsUK

AF:

0.0734

AC:

272

ALSPAC

AF:

0.0698

AC:

269

ESP6500AA

AF:

0.107

AC:

397

ESP6500EA

AF:

0.0950

AC:

779

ExAC

AF:

0.128

AC:

15425

Asia WGS

AF:

0.241

AC:

836

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Netherton syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Ichthyosis linearis circumflexa

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.0

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.46

T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.;M

PhyloP100

-0.62

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.77

N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Vest4

0.086

ClinPred

0.0061

GERP RS

0.56

Varity_R

0.10

gMVP

0.23

Mutation Taster

=99/1

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