rs17860502

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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:3O:1

Conservation

PhyloP100: 0.0900

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:

LOC124901185 (HGNC:):

LOC124901185 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 139254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148086438-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.316G>A	p.Asp106Asn	missense_variant	5/33	ENST00000256084.8
LOC124901185	XR_007059139.1 linkuse as main transcript	n.612-1997C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.316G>A	p.Asp106Asn	missense_variant	5/33	1	NM_006846.4	P2	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

GnomAD3 exomes

AF:

0.0455

AC:

11326

AN:

248808

Hom.:

401

AF XY:

0.0455

AC XY:

6137

AN XY:

134988

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 SAS exome

AF:

0.0628

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

Gnomad4 AFR exome

AF:

0.00504

Gnomad4 AMR exome

AF:

0.0538

Gnomad4 ASJ exome

AF:

0.0312

Gnomad4 EAS exome

AF:

0.160

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.0527

Gnomad4 NFE exome

AF:

0.0339

Gnomad4 OTH exome

AF:

0.0374

GnomAD4 genome

AF:

0.0339

AC:

5158

AN:

151964

Hom.:

151

Cov.:

AF XY:

0.0369

AC XY:

2739

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00701

Gnomad4 AMR

AF:

0.0544

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.0680

Gnomad4 FIN

AF:

0.0577

Gnomad4 NFE

AF:

0.0335

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0342

Hom.:

222

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:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2014

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. -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Netherton syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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

Dann

Benign

0.90

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

MutationTaster

Benign

1.0

N;N;N

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over