rs3752677

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.209+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,610,056 control chromosomes in the GnomAD database, including 1,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 201 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1692 hom. )

Consequence

SPINK5
NM_006846.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.301

Publications

6 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:

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 (BayesDel_noAF=-0.85).

BP6

Variant 5-148070465-C-T is Benign according to our data. Variant chr5-148070465-C-T is described in ClinVar as [Benign]. Clinvar id is 260048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.209+15C>T		intron_variant	Intron 3 of 32	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.209+15C>T		intron_variant	Intron 3 of 32	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0467

AC:

7101

AN:

151970

Hom.:

200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0521

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0580

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.0667

Gnomad FIN

AF:

0.0577

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0487

AC:

12063

AN:

247910

AF XY:

0.0478

show subpopulations

Gnomad AFR exome

AF:

0.0491

Gnomad AMR exome

AF:

0.0549

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0379

GnomAD4 exome

AF:

0.0408

AC:

59552

AN:

1457968

Hom.:

1692

Cov.:

AF XY:

0.0411

AC XY:

29825

AN XY:

725366

show subpopulations

African (AFR)

AF:

0.0515

AC:

1717

AN:

33342

American (AMR)

AF:

0.0556

AC:

2473

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

811

AN:

25990

East Asian (EAS)

AF:

0.160

AC:

6309

AN:

39478

South Asian (SAS)

AF:

0.0616

AC:

5305

AN:

86120

European-Finnish (FIN)

AF:

0.0529

AC:

2816

AN:

53250

Middle Eastern (MID)

AF:

0.00785

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0340

AC:

37669

AN:

1109426

Other (OTH)

AF:

0.0400

AC:

2407

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2750

5500

8251

11001

13751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0468

AC:

7111

AN:

152088

Hom.:

201

Cov.:

AF XY:

0.0493

AC XY:

3666

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0520

AC:

2160

AN:

41524

American (AMR)

AF:

0.0582

AC:

888

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3466

East Asian (EAS)

AF:

0.125

AC:

640

AN:

5134

South Asian (SAS)

AF:

0.0676

AC:

326

AN:

4820

European-Finnish (FIN)

AF:

0.0577

AC:

611

AN:

10584

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0337

AC:

2293

AN:

67976

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

349

698

1046

1395

1744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0384

Hom.:

Bravo

AF:

0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

- -

Netherton syndrome

Benign:1

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:1

Mar 03, 2015

GeneDx

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

-0.85

CADD

Benign

6.0

(source)

DANN

Benign

0.57

PhyloP100

-0.30

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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rs3752677

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