Variant 5-148120311-GAAA-GAA details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006846.4(SPINK5):c.2468delA(p.Lys823fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,528,082 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 0.000021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

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:):

FBXO38-DT links:

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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-GA-G is Pathogenic according to our data. Variant chr5-148120311-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 523932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2468delA	p.Lys823fs	frameshift_variant	26/33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.2468delA	p.Lys823fs	frameshift_variant	26/33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

146004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00406

AC:

534

AN:

131578

Hom.:

AF XY:

0.00435

AC XY:

305

AN XY:

70102

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00227

Gnomad EAS exome

AF:

0.00417

Gnomad SAS exome

AF:

0.00538

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00318

GnomAD4 exome

AF:

0.000228

AC:

315

AN:

1382014

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

173

AN XY:

686958

show subpopulations

Gnomad4 AFR exome

AF:

0.000289

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.000164

Gnomad4 EAS exome

AF:

0.000513

Gnomad4 SAS exome

AF:

0.000770

Gnomad4 FIN exome

AF:

0.000138

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.000159

GnomAD4 genome

AF:

0.0000205

AC:

AN:

146068

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70858

show subpopulations

Gnomad4 AFR

AF:

0.0000251

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000219

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00549

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Netherton syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_006846.3:c.2468delA in the SPINK5 gene has an allele frequency of 0.005 in South subpopulation in the gnomAD database. This variant has been reported previously in individuals with Netherton syndrome, including one compound heterozygote 1608-1G>A/2468delA and one homozygote (PMID: 11841556). The c.2468delA variant causes a frameshift starting with codon Lysine 823, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 101 of the new reading frame, denoted p.Lys823Argfs*101. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PM3_Strong+PP4 -

Ichthyosis linearis circumflexa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys823Argfs*101) 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 individual(s) with Netherton syndrome (PMID: 11841556, 12923596, 26229701). ClinVar contains an entry for this variant (Variation ID: 523932). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12923596, 27905021, 11841556, 26229701, 36262015, 31980526) -

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