rs6892205

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.800A>G(p.Gln267Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,607,930 control chromosomes in the GnomAD database, including 215,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q267H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.51 ( 19668 hom., cov: 31)

Exomes 𝑓: 0.52 ( 195529 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -3.98

Publications

45 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.1259713E-6).

BP6

Variant 5-148095823-A-G is Benign according to our data. Variant chr5-148095823-A-G is described in ClinVar as [Benign]. Clinvar id is 139256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.800A>G	p.Gln267Arg	missense_variant	Exon 10 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.800A>G	p.Gln267Arg	missense_variant	Exon 10 of 33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76829

AN:

151480

Hom.:

19656

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.605

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.489

Gnomad FIN

AF:

0.533

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.521

GnomAD2 exomes

AF:

0.532

AC:

132330

AN:

248824

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.459

Gnomad AMR exome

AF:

0.709

Gnomad ASJ exome

AF:

0.457

Gnomad EAS exome

AF:

0.478

Gnomad FIN exome

AF:

0.546

Gnomad NFE exome

AF:

0.513

Gnomad OTH exome

AF:

0.527

GnomAD4 exome

AF:

0.515

AC:

750408

AN:

1456332

Hom.:

195529

Cov.:

AF XY:

0.513

AC XY:

372040

AN XY:

724698

show subpopulations

African (AFR)

AF:

0.454

AC:

15097

AN:

33282

American (AMR)

AF:

0.695

AC:

30945

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.456

AC:

11878

AN:

26028

East Asian (EAS)

AF:

0.451

AC:

17850

AN:

39610

South Asian (SAS)

AF:

0.487

AC:

41938

AN:

86146

European-Finnish (FIN)

AF:

0.545

AC:

29052

AN:

53324

Middle Eastern (MID)

AF:

0.519

AC:

2965

AN:

5712

European-Non Finnish (NFE)

AF:

0.515

AC:

569918

AN:

1107590

Other (OTH)

AF:

0.512

AC:

30765

AN:

60084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

18525

37050

55576

74101

92626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.507

AC:

76871

AN:

151598

Hom.:

19668

Cov.:

AF XY:

0.510

AC XY:

37743

AN XY:

74066

show subpopulations

African (AFR)

AF:

0.458

AC:

18930

AN:

41376

American (AMR)

AF:

0.605

AC:

9192

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

1558

AN:

3468

East Asian (EAS)

AF:

0.475

AC:

2424

AN:

5106

South Asian (SAS)

AF:

0.491

AC:

2360

AN:

4810

European-Finnish (FIN)

AF:

0.533

AC:

5601

AN:

10518

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.518

AC:

35101

AN:

67824

Other (OTH)

AF:

0.521

AC:

1098

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1925

3850

5774

7699

9624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.513

Hom.:

77598

Bravo

AF:

0.514

TwinsUK

AF:

0.526

AC:

1952

ALSPAC

AF:

0.521

AC:

2008

ESP6500AA

AF:

0.460

AC:

1667

ESP6500EA

AF:

0.508

AC:

4132

ExAC

AF:

0.521

AC:

62900

Asia WGS

AF:

0.533

AC:

1846

AN:

3476

EpiCase

AF:

0.514

EpiControl

AF:

0.524

ClinVar

Significance: Benign

Submissions summary: Benign:6Other: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

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary 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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 75. 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 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 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

0.064

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.027

.;.;.;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.17

T;T;T;T

MetaRNN

Benign

0.0000051

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.59

N;N;.;N

PhyloP100

-4.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.090

N;N;N;N

REVEL

Benign

0.047

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.019

MPC

0.10

ClinPred

0.0035

GERP RS

-7.6

Varity_R

0.051

gMVP

0.23

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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rs6892205

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