5-148120311-GAAA-GAAAA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006846.4(SPINK5):c.2468dupA(p.Lys824GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,361,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPINK5
NM_006846.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.94

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-148120311-G-GA is Pathogenic according to our data. Variant chr5-148120311-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 5268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2468dupA	p.Lys824GlufsTer4	frameshift_variant	Exon 26 of 33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.2468dupA	p.Lys824GlufsTer4	frameshift_variant	Exon 26 of 33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146014

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000274

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000906

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00133

AC:

175

AN:

131578

Hom.:

AF XY:

0.00120

AC XY:

AN XY:

70102

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.000698

Gnomad EAS exome

AF:

0.00184

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000378

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.000318

GnomAD4 exome

AF:

0.000220

AC:

299

AN:

1361340

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

143

AN XY:

676992

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000593

Gnomad4 ASJ exome

AF:

0.000250

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000259

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.000161

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000103

AC:

AN:

146078

Hom.:

Cov.:

AF XY:

0.0000847

AC XY:

AN XY:

70866

show subpopulations

Gnomad4 AFR

AF:

0.000125

Gnomad4 AMR

AF:

0.000274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000906

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Netherton syndrome

Pathogenic:3

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.113%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005268 / PMID: 10835624). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ichthyosis linearis circumflexa

Pathogenic:2

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPINK5 c.2468dupA (p.Lys824GlufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0013 in 131578 control chromosomes (gnomAD). c.2468dupA (aka 2468insA) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Netherton syndrome (e.g. Chavanas_2000, Bitoun_2002). These publications also reported dramatic reduction in the SPINK5 mRNA in keratinocytes derived from homozygous patients, suggestive of nonsense-mediated mRNA decay (Bitoun_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10835624, 11841556). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys824Glufs*4) in the SPINK5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK5 are known to be pathogenic (PMID: 11511292, 11841556). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Netherton syndrome (PMID: 10835624, 26031502). This variant is also known as 2468insA. ClinVar contains an entry for this variant (Variation ID: 5268). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Oct 26, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2468dupA pathogenic variant in the SPINK5 gene has been reported previously in the homozygous state or as a single variant in patients with Netherton syndrome (Chavanas et al., 2000; Bitoun et al., 2002; Raghunath et al., 2004). It causes a frameshift starting with codon Lysine 824, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Lys824GlufsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2468dupA variant is observed in 17/7814 (0.22%) alleles from individuals of African background, in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.2468dupA as a pathogenic variant. -

Feb 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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