rs2303064

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006846.4(SPINK5):c.1156G>A(p.Asp386Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,950 control chromosomes in the GnomAD database, including 30,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6884 hom., cov: 32)

Exomes 𝑓: 0.15 ( 23885 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 2.67

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:

SPINK5 (HGNC:):

SPINK5 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=0.0070517957).

BP6

Variant 5-148100517-G-A is Benign according to our data. Variant chr5-148100517-G-A is described in ClinVar as [Benign]. Clinvar id is 139258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148100517-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.1156G>A	p.Asp386Asn	missense_variant	13/33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.1156G>A	p.Asp386Asn	missense_variant	13/33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37827

AN:

151836

Hom.:

6874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.440

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.225

GnomAD3 exomes

AF:

0.204

AC:

50931

AN:

249156

Hom.:

7514

AF XY:

0.205

AC XY:

27699

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.356

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.151

AC:

220585

AN:

1460996

Hom.:

23885

Cov.:

AF XY:

0.156

AC XY:

113573

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.504

Gnomad4 AMR exome

AF:

0.140

Gnomad4 ASJ exome

AF:

0.210

Gnomad4 EAS exome

AF:

0.464

Gnomad4 SAS exome

AF:

0.353

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.177

GnomAD4 genome

AF:

0.249

AC:

37869

AN:

151954

Hom.:

6884

Cov.:

AF XY:

0.254

AC XY:

18848

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.497

Gnomad4 AMR

AF:

0.172

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.440

Gnomad4 SAS

AF:

0.361

Gnomad4 FIN

AF:

0.148

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.225

Alfa

AF:

0.151

Hom.:

6205

Bravo

AF:

0.259

TwinsUK

AF:

0.105

AC:

391

ALSPAC

AF:

0.107

AC:

413

ESP6500AA

AF:

0.458

AC:

1800

ESP6500EA

AF:

0.125

AC:

1044

ExAC

AF:

0.212

AC:

25584

Asia WGS

AF:

0.348

AC:

1211

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 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. -

Netherton syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

Uncertain

0.36

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

.;.;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0071

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L;.;L

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.090

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.086

T;D;T;D

Polyphen

0.40

B;P;.;P

Vest4

0.23

MPC

0.21

ClinPred

0.011

GERP RS

3.8

Varity_R

0.13

gMVP

0.32

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