rs142227576

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006846.4(SPINK5):c.1964G>A(p.Gly655Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,640 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G655S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 10 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.51

Publications

13 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01426217).

BP6

Variant 5-148114438-G-A is Benign according to our data. Variant chr5-148114438-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418504.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	NM_006846.4	MANE Select	c.1964G>A	p.Gly655Asp	missense	Exon 21 of 33	NP_006837.2	Q9NQ38-1
SPINK5	NM_001127698.2		c.1964G>A	p.Gly655Asp	missense	Exon 21 of 34	NP_001121170.1	Q9NQ38-3
SPINK5	NM_001127699.2		c.1964G>A	p.Gly655Asp	missense	Exon 21 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1964G>A	p.Gly655Asp	missense	Exon 21 of 33	ENSP00000256084.7	Q9NQ38-1
SPINK5	ENST00000359874.7	TSL:1	c.1964G>A	p.Gly655Asp	missense	Exon 21 of 34	ENSP00000352936.3	Q9NQ38-3
SPINK5	ENST00000398454.5	TSL:1	c.1964G>A	p.Gly655Asp	missense	Exon 21 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

450

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00484

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00263

AC:

655

AN:

249394

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00372

AC:

5441

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

2627

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33460

American (AMR)

AF:

0.00226

AC:

101

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00299

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00139

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00448

AC:

4981

AN:

1111696

Other (OTH)

AF:

0.00298

AC:

180

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

304

608

912

1216

1520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<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:

0.00296

AC:

450

AN:

152226

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

194

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41546

American (AMR)

AF:

0.00379

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00484

AC:

329

AN:

68014

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00405

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00386

AC:

ExAC

AF:

0.00255

AC:

308

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00439

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Netherton syndrome (2)

not provided (2)

Ichthyosis linearis circumflexa (1)

SPINK5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

M_CAP

Benign

0.014

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.8

PhyloP100

2.5

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.37

MVP

0.49

MPC

0.56

ClinPred

0.030

GERP RS

5.4

Varity_R

0.52

gMVP

0.88

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over