rs2303065

Positions:

chr5-148100549-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.1188T>C(p.His396=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,612,000 control chromosomes in the GnomAD database, including 213,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16511 hom., cov: 32)

Exomes 𝑓: 0.52 ( 196990 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.168

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 5-148100549-T-C is Benign according to our data. Variant chr5-148100549-T-C is described in ClinVar as [Benign]. Clinvar id is 139259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148100549-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.168 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.1188T>C	p.His396=	synonymous_variant	13/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.1188T>C	p.His396=	synonymous_variant	13/33	1	NM_006846.4	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-6807A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.447

AC:

67909

AN:

151836

Hom.:

16501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.524

Gnomad OTH

AF:

0.474

GnomAD3 exomes

AF:

0.520

AC:

129643

AN:

249100

Hom.:

35214

AF XY:

0.519

AC XY:

70080

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.700

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.475

Gnomad SAS exome

AF:

0.487

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.524

GnomAD4 exome

AF:

0.515

AC:

751974

AN:

1460046

Hom.:

196990

Cov.:

AF XY:

0.514

AC XY:

373320

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.685

Gnomad4 ASJ exome

AF:

0.461

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.489

Gnomad4 FIN exome

AF:

0.549

Gnomad4 NFE exome

AF:

0.522

Gnomad4 OTH exome

AF:

0.502

GnomAD4 genome

AF:

0.447

AC:

67931

AN:

151954

Hom.:

16511

Cov.:

AF XY:

0.451

AC XY:

33478

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.238

Gnomad4 AMR

AF:

0.580

Gnomad4 ASJ

AF:

0.454

Gnomad4 EAS

AF:

0.473

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.535

Gnomad4 NFE

AF:

0.524

Gnomad4 OTH

AF:

0.476

Alfa

AF:

0.506

Hom.:

10168

Bravo

AF:

0.445

Asia WGS

AF:

0.520

AC:

1802

AN:

3476

EpiCase

AF:

0.518

EpiControl

AF:

0.531

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Netherton syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.5

DANN

Benign

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over