rs17718737

Positions:

chr5-148112898-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.1851T>C(p.Ala617Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,784 control chromosomes in the GnomAD database, including 1,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 152 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1630 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.119

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=-0.88).

BP6

Variant 5-148112898-T-C is Benign according to our data. Variant chr5-148112898-T-C is described in ClinVar as [Benign]. Clinvar id is 139261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.119 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.1851T>C	p.Ala617Ala	synonymous_variant	20/33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.1851T>C	p.Ala617Ala	synonymous_variant	20/33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0364

AC:

5537

AN:

152076

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0545

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.0619

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0254

GnomAD3 exomes

AF:

0.0453

AC:

11278

AN:

248832

Hom.:

375

AF XY:

0.0453

AC XY:

6115

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.0535

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.114

Gnomad SAS exome

AF:

0.0615

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0343

GnomAD4 exome

AF:

0.0398

AC:

58234

AN:

1461590

Hom.:

1630

Cov.:

AF XY:

0.0402

AC XY:

29255

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.0541

Gnomad4 ASJ exome

AF:

0.0267

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.0605

Gnomad4 FIN exome

AF:

0.0529

Gnomad4 NFE exome

AF:

0.0341

Gnomad4 OTH exome

AF:

0.0379

GnomAD4 genome

AF:

0.0364

AC:

5540

AN:

152194

Hom.:

152

Cov.:

AF XY:

0.0389

AC XY:

2891

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0178

Gnomad4 AMR

AF:

0.0547

Gnomad4 ASJ

AF:

0.0276

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.0624

Gnomad4 FIN

AF:

0.0575

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0325

Hom.:

Bravo

AF:

0.0346

Asia WGS

AF:

0.0830

AC:

288

AN:

3476

EpiCase

AF:

0.0305

EpiControl

AF:

0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Netherton syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

-0.88

CADD

Benign

6.3

DANN

Benign

0.41

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

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