5-148123955-C-G

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.2661C>G(p.Ser887Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00754 in 1,613,774 control chromosomes in the GnomAD database, including 760 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 412 hom., cov: 31)

Exomes 𝑓: 0.0042 ( 348 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.404

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=0.0016739666).

BP6

Variant 5-148123955-C-G is Benign according to our data. Variant chr5-148123955-C-G is described in ClinVar as Benign. ClinVar VariationId is 260052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

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
SPINK5	NM_006846.4	MANE Select	c.2661C>G	p.Ser887Arg	missense	Exon 27 of 33	NP_006837.2
SPINK5	NM_001127698.2		c.2661C>G	p.Ser887Arg	missense	Exon 27 of 34	NP_001121170.1
SPINK5	NM_001127699.2		c.2661C>G	p.Ser887Arg	missense	Exon 27 of 28	NP_001121171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2661C>G	p.Ser887Arg	missense	Exon 27 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.2661C>G	p.Ser887Arg	missense	Exon 27 of 34	ENSP00000352936.3
SPINK5	ENST00000398454.5	TSL:1	c.2661C>G	p.Ser887Arg	missense	Exon 27 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes

AF:

0.0398

AC:

6052

AN:

152054

Hom.:

412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0104

AC:

2596

AN:

249004

AF XY:

0.00816

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.00748

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000275

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.00418

AC:

6107

AN:

1461602

Hom.:

348

Cov.:

AF XY:

0.00354

AC XY:

2577

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.143

AC:

4783

AN:

33446

American (AMR)

AF:

0.00883

AC:

395

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000348

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000234

AC:

260

AN:

1111896

Other (OTH)

AF:

0.00979

AC:

591

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

300

600

900

1200

1500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0398

AC:

6062

AN:

152172

Hom.:

412

Cov.:

AF XY:

0.0390

AC XY:

2900

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.138

AC:

5728

AN:

41484

American (AMR)

AF:

0.0160

AC:

244

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68000

Other (OTH)

AF:

0.0257

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

263

526

788

1051

1314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0116

Hom.:

Bravo

AF:

0.0467

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.142

AC:

532

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.0126

AC:

1524

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis linearis circumflexa (1)

Netherton syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.40

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.084

Sift

Benign

0.056

Sift4G

Benign

0.21

Polyphen

0.98

Vest4

0.28

MutPred

0.44

Gain of MoRF binding (P = 0.0067)

MPC

0.13

ClinPred

0.0069

GERP RS

2.6

Varity_R

0.10

gMVP

0.38

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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