5-148127020-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006846.4(SPINK5):c.2905A>G(p.Lys969Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,724 control chromosomes in the GnomAD database, including 31 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 0.0079 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 20 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.187

Publications

5 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=0.0022529662).

BP6

Variant 5-148127020-A-G is Benign according to our data. Variant chr5-148127020-A-G is described in ClinVar as Benign. ClinVar VariationId is 351540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00791 (1205/152300) while in subpopulation AFR AF = 0.0232 (966/41556). AF 95% confidence interval is 0.022. There are 11 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2905A>G	p.Lys969Glu	missense	Exon 30 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.2995A>G	p.Lys999Glu	missense	Exon 31 of 34	NP_001121170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2905A>G	p.Lys969Glu	missense	Exon 30 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.2995A>G	p.Lys999Glu	missense	Exon 31 of 34	ENSP00000352936.3
FBXO38-DT	ENST00000667608.1		n.1257-33278T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00792

AC:

1205

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00862

GnomAD2 exomes

AF:

0.00252

AC:

627

AN:

249086

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00251

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00129

AC:

1884

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

910

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0225

AC:

751

AN:

33418

American (AMR)

AF:

0.00175

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000766

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000128

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00225

AC:

120

AN:

53390

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000703

AC:

782

AN:

1111834

Other (OTH)

AF:

0.00197

AC:

119

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00791

AC:

1205

AN:

152300

Hom.:

Cov.:

AF XY:

0.00716

AC XY:

533

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0232

AC:

966

AN:

41556

American (AMR)

AF:

0.00516

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

68034

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00359

Hom.:

Bravo

AF:

0.00849

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.00147

AC:

ExAC

AF:

0.00285

AC:

344

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Ichthyosis linearis circumflexa (1)

Netherton syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.3

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.10

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.17

PhyloP100

0.19

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.34

REVEL

Benign

0.022

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.0010

Vest4

0.14

MVP

0.21

MPC

0.14

ClinPred

0.00062

GERP RS

0.51

Varity_R

0.072

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over