rs2303063

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127698.2(SPINK5):c.1103G>A(p.Ser368Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,595,430 control chromosomes in the GnomAD database, including 212,859 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 (★★).

Frequency

Genomes: 𝑓 0.45 ( 16486 hom., cov: 32)

Exomes 𝑓: 0.51 ( 196373 hom. )

Consequence

SPINK5
NM_001127698.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0190

Publications

51 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=6.628441E-6).

BP6

Variant 5-148100464-G-A is Benign according to our data. Variant chr5-148100464-G-A is described in ClinVar as Benign. ClinVar VariationId is 260043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127698.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	NM_006846.4	MANE Select	c.1103G>A	p.Ser368Asn	missense	Exon 13 of 33	NP_006837.2
SPINK5	NM_001127698.2		c.1103G>A	p.Ser368Asn	missense	Exon 13 of 34	NP_001121170.1
SPINK5	NM_001127699.2		c.1103G>A	p.Ser368Asn	missense	Exon 13 of 28	NP_001121171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1103G>A	p.Ser368Asn	missense	Exon 13 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.1103G>A	p.Ser368Asn	missense	Exon 13 of 34	ENSP00000352936.3
SPINK5	ENST00000398454.5	TSL:1	c.1103G>A	p.Ser368Asn	missense	Exon 13 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67838

AN:

151714

Hom.:

16476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.581

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.534

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.524

Gnomad OTH

AF:

0.474

GnomAD2 exomes

AF:

0.520

AC:

129366

AN:

248890

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.700

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.474

Gnomad FIN exome

AF:

0.547

Gnomad NFE exome

AF:

0.519

Gnomad OTH exome

AF:

0.523

GnomAD4 exome

AF:

0.514

AC:

742660

AN:

1443598

Hom.:

196373

Cov.:

AF XY:

0.513

AC XY:

369137

AN XY:

719046

show subpopulations

African (AFR)

AF:

0.227

AC:

7527

AN:

33182

American (AMR)

AF:

0.685

AC:

30560

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

11970

AN:

25948

East Asian (EAS)

AF:

0.446

AC:

17665

AN:

39570

South Asian (SAS)

AF:

0.489

AC:

42018

AN:

85982

European-Finnish (FIN)

AF:

0.547

AC:

29168

AN:

53288

Middle Eastern (MID)

AF:

0.509

AC:

2917

AN:

5730

European-Non Finnish (NFE)

AF:

0.521

AC:

570910

AN:

1095534

Other (OTH)

AF:

0.501

AC:

29925

AN:

59720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

Heterozygous variant carriers

16493

32986

49478

65971

82464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16174

32348

48522

64696

80870

<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:

0.447

AC:

67860

AN:

151832

Hom.:

16486

Cov.:

AF XY:

0.451

AC XY:

33424

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.237

AC:

9830

AN:

41414

American (AMR)

AF:

0.581

AC:

8846

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

1576

AN:

3470

East Asian (EAS)

AF:

0.474

AC:

2431

AN:

5128

South Asian (SAS)

AF:

0.492

AC:

2366

AN:

4810

European-Finnish (FIN)

AF:

0.534

AC:

5616

AN:

10516

Middle Eastern (MID)

AF:

0.493

AC:

144

AN:

292

European-Non Finnish (NFE)

AF:

0.524

AC:

35583

AN:

67954

Other (OTH)

AF:

0.476

AC:

1005

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1788

3575

5363

7150

8938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

0.494

Hom.:

56986

Bravo

AF:

0.445

TwinsUK

AF:

0.528

AC:

1959

ALSPAC

AF:

0.526

AC:

2027

ESP6500AA

AF:

0.251

AC:

960

ESP6500EA

AF:

0.511

AC:

4223

ExAC

AF:

0.506

AC:

61104

Asia WGS

AF:

0.518

AC:

1798

AN:

3478

EpiCase

AF:

0.518

EpiControl

AF:

0.530

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Netherton syndrome (2)

Ichthyosis linearis circumflexa (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.4

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.13

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.072

MetaRNN

Benign

0.0000066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

-0.019

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.50

REVEL

Benign

0.022

Sift

Benign

0.83

Sift4G

Benign

0.69

Polyphen

0.0070

Vest4

0.11

MPC

0.095

ClinPred

0.0018

GERP RS

2.4

Varity_R

0.035

gMVP

0.45

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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