5-148120053-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.2358C>T(p.Leu786Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,612,812 control chromosomes in the GnomAD database, including 295,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23521 hom., cov: 32)

Exomes 𝑓: 0.61 ( 272377 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.75

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 5-148120053-C-T is Benign according to our data. Variant chr5-148120053-C-T is described in ClinVar as Benign. ClinVar VariationId is 260050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2358C>T	p.Leu786Leu	synonymous_variant	Exon 25 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.2358C>T	p.Leu786Leu	synonymous_variant	Exon 25 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82404

AN:

151940

Hom.:

23498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.594

Gnomad AMR

AF:

0.640

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.504

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.629

Gnomad OTH

AF:

0.545

GnomAD2 exomes

AF:

0.593

AC:

147752

AN:

248974

AF XY:

0.589

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.742

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.460

Gnomad FIN exome

AF:

0.641

Gnomad NFE exome

AF:

0.621

Gnomad OTH exome

AF:

0.595

GnomAD4 exome

AF:

0.607

AC:

885957

AN:

1460754

Hom.:

272377

Cov.:

AF XY:

0.604

AC XY:

438680

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.345

AC:

11555

AN:

33460

American (AMR)

AF:

0.726

AC:

32478

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

14364

AN:

26122

East Asian (EAS)

AF:

0.437

AC:

17350

AN:

39684

South Asian (SAS)

AF:

0.509

AC:

43905

AN:

86224

European-Finnish (FIN)

AF:

0.642

AC:

34268

AN:

53398

Middle Eastern (MID)

AF:

0.534

AC:

3077

AN:

5766

European-Non Finnish (NFE)

AF:

0.624

AC:

693658

AN:

1111034

Other (OTH)

AF:

0.585

AC:

35302

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

18309

36618

54927

73236

91545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18404

36808

55212

73616

92020

<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:

0.542

AC:

82467

AN:

152058

Hom.:

23521

Cov.:

AF XY:

0.542

AC XY:

40292

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.353

AC:

14635

AN:

41452

American (AMR)

AF:

0.640

AC:

9790

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1874

AN:

3472

East Asian (EAS)

AF:

0.470

AC:

2431

AN:

5168

South Asian (SAS)

AF:

0.506

AC:

2437

AN:

4820

European-Finnish (FIN)

AF:

0.632

AC:

6677

AN:

10566

Middle Eastern (MID)

AF:

0.517

AC:

152

AN:

294

European-Non Finnish (NFE)

AF:

0.629

AC:

42780

AN:

67978

Other (OTH)

AF:

0.546

AC:

1153

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1876

3751

5627

7502

9378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.598

Hom.:

25063

Bravo

AF:

0.536

Asia WGS

AF:

0.528

AC:

1832

AN:

3478

EpiCase

AF:

0.617

EpiControl

AF:

0.616

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -

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

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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. -

not provided

Benign:1Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.5

(source)

DANN

Benign

0.66

PhyloP100

-2.7

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over