Genetic Variant SPINK5:c.-182-66G>A (chr5-148063797-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000521206.5(SPINK5):c.-182-66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 567,076 control chromosomes in the GnomAD database, including 878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 149 hom., cov: 32)

Exomes 𝑓: 0.046 ( 729 hom. )

Consequence

SPINK5
ENST00000521206.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 5-148063797-G-A is Benign according to our data. Variant chr5-148063797-G-A is described in ClinVar as [Benign]. Clinvar id is 1165060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.-248G>A	upstream_gene_variant	ENST00000256084.8	NP_006837.2	Q9NQ38-1
SPINK5	NM_001127698.2 link	c.-248G>A	upstream_gene_variant		NP_001121170.1	Q9NQ38-3
SPINK5	NM_001127699.2 link	c.-248G>A	upstream_gene_variant		NP_001121171.1	Q9NQ38-2
SPINK5	XM_047416662.1 link	c.-248G>A	upstream_gene_variant		XP_047272618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.-248G>A		upstream_gene_variant		1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5138

AN:

151980

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00694

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0538

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.0666

Gnomad FIN

AF:

0.0574

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0335

Gnomad OTH

AF:

0.0239

GnomAD4 exome

AF:

0.0460

AC:

19072

AN:

414978

Hom.:

729

AF XY:

0.0459

AC XY:

10087

AN XY:

219976

show subpopulations

Gnomad4 AFR exome

AF:

0.00676

Gnomad4 AMR exome

AF:

0.0545

Gnomad4 ASJ exome

AF:

0.0298

Gnomad4 EAS exome

AF:

0.162

Gnomad4 SAS exome

AF:

0.0610

Gnomad4 FIN exome

AF:

0.0539

Gnomad4 NFE exome

AF:

0.0327

Gnomad4 OTH exome

AF:

0.0361

GnomAD4 genome

AF:

0.0338

AC:

5144

AN:

152098

Hom.:

149

Cov.:

AF XY:

0.0367

AC XY:

2725

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00692

Gnomad4 AMR

AF:

0.0540

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.0675

Gnomad4 FIN

AF:

0.0574

Gnomad4 NFE

AF:

0.0335

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0316

Hom.:

Bravo

AF:

0.0312

Asia WGS

AF:

0.0850

AC:

296

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19534795) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.053

DANN

Benign

0.67

Splicing

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