NM_006846.4:c.316G>A

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.316G>A(p.Asp106Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,611,568 control chromosomes in the GnomAD database, including 1,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D106V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 151 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1635 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.0900

Publications

22 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 Gene-Disease associations (from GenCC):

Netherton syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P

SPINK5 links:

LOC124901185 (HGNC:):

LOC124901185 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=0.0030230284).

BP6

Variant 5-148086438-G-A is Benign according to our data. Variant chr5-148086438-G-A is described in ClinVar as Benign. ClinVar VariationId is 139254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 5 of 33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 5 of 33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5152

AN:

151846

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00703

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0542

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.0671

Gnomad FIN

AF:

0.0577

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0335

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0455

AC:

11326

AN:

248808

AF XY:

0.0455

show subpopulations

Gnomad AFR exome

AF:

0.00428

Gnomad AMR exome

AF:

0.0535

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0355

GnomAD4 exome

AF:

0.0396

AC:

57828

AN:

1459604

Hom.:

1635

Cov.:

AF XY:

0.0401

AC XY:

29117

AN XY:

726136

show subpopulations

African (AFR)

AF:

0.00504

AC:

168

AN:

33324

American (AMR)

AF:

0.0538

AC:

2401

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

812

AN:

26056

East Asian (EAS)

AF:

0.160

AC:

6329

AN:

39598

South Asian (SAS)

AF:

0.0618

AC:

5326

AN:

86192

European-Finnish (FIN)

AF:

0.0527

AC:

2797

AN:

53096

Middle Eastern (MID)

AF:

0.00749

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0339

AC:

37701

AN:

1110738

Other (OTH)

AF:

0.0374

AC:

2251

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2732

5463

8195

10926

13658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1526

3052

4578

6104

7630

<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:

0.0339

AC:

5158

AN:

151964

Hom.:

151

Cov.:

AF XY:

0.0369

AC XY:

2739

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00701

AC:

291

AN:

41502

American (AMR)

AF:

0.0544

AC:

829

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3464

East Asian (EAS)

AF:

0.126

AC:

644

AN:

5116

South Asian (SAS)

AF:

0.0680

AC:

328

AN:

4824

European-Finnish (FIN)

AF:

0.0577

AC:

613

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0335

AC:

2276

AN:

67882

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

241

481

722

962

1203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0350

Hom.:

497

Bravo

AF:

0.0311

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.00597

AC:

ESP6500EA

AF:

0.0307

AC:

252

ExAC

AF:

0.0442

AC:

5337

Asia WGS

AF:

0.0850

AC:

295

AN:

3478

EpiCase

AF:

0.0301

EpiControl

AF:

0.0269

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Netherton syndrome

Benign:2

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 13, 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

- -

not specified

Benign:1

Jan 08, 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. -

not provided

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.7

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.084

.;.;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.65

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.3

L;L;.;L

PhyloP100

0.090

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.90

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.38

T;T;T;T

Sift4G

Benign

0.66

T;T;T;T

Polyphen

0.0050

B;B;.;B

Vest4

0.089

MPC

0.095

ClinPred

0.00098

GERP RS

2.8

Varity_R

0.036

gMVP

0.21

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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