rs880687

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.1557C>A(p.Gly519Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,612,412 control chromosomes in the GnomAD database, including 213,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G519G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.44 ( 16395 hom., cov: 31)

Exomes 𝑓: 0.51 ( 196802 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.271

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-148107114-C-A is Benign according to our data. Variant chr5-148107114-C-A is described in ClinVar as Benign. ClinVar VariationId is 260047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.271 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.1557C>A	p.Gly519Gly	synonymous_variant	Exon 17 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.1557C>A	p.Gly519Gly	synonymous_variant	Exon 17 of 33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67528

AN:

151736

Hom.:

16385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.524

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.520

AC:

129650

AN:

249522

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.227

Gnomad AMR exome

AF:

0.700

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.523

GnomAD4 exome

AF:

0.515

AC:

751623

AN:

1460560

Hom.:

196802

Cov.:

AF XY:

0.514

AC XY:

373182

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.219

AC:

7325

AN:

33444

American (AMR)

AF:

0.684

AC:

30571

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12037

AN:

26088

East Asian (EAS)

AF:

0.447

AC:

17698

AN:

39624

South Asian (SAS)

AF:

0.489

AC:

42169

AN:

86228

European-Finnish (FIN)

AF:

0.547

AC:

29158

AN:

53300

Middle Eastern (MID)

AF:

0.510

AC:

2932

AN:

5754

European-Non Finnish (NFE)

AF:

0.522

AC:

579536

AN:

1111158

Other (OTH)

AF:

0.501

AC:

30197

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

21258

42516

63774

85032

106290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16604

33208

49812

66416

83020

<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:

0.445

AC:

67549

AN:

151852

Hom.:

16395

Cov.:

AF XY:

0.449

AC XY:

33304

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.229

AC:

9506

AN:

41440

American (AMR)

AF:

0.580

AC:

8846

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1577

AN:

3466

East Asian (EAS)

AF:

0.475

AC:

2436

AN:

5124

South Asian (SAS)

AF:

0.492

AC:

2366

AN:

4812

European-Finnish (FIN)

AF:

0.535

AC:

5635

AN:

10524

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.524

AC:

35574

AN:

67932

Other (OTH)

AF:

0.475

AC:

1003

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1775

3551

5326

7102

8877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.495

Hom.:

55727

Bravo

AF:

0.442

Asia WGS

AF:

0.519

AC:

1800

AN:

3478

EpiCase

AF:

0.518

EpiControl

AF:

0.530

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

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

- -

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

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. -

not provided

Benign:1Other: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. -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.85

(source)

DANN

Benign

0.41

PhyloP100

-0.27

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over