Genetic Variant SPINK5:c.2313+31C>G (chr5-148119089-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_006846.4(SPINK5):c.2313+31C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,603,952 control chromosomes in the GnomAD database, including 476,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 48085 hom., cov: 31)

Exomes 𝑓: 0.77 ( 428904 hom. )

Consequence

SPINK5
NM_006846.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0540

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 5-148119089-C-G is Benign according to our data. Variant chr5-148119089-C-G is described in ClinVar as [Benign]. Clinvar id is 1182656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2313+31C>G		intron_variant	Intron 24 of 32	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.2313+31C>G		intron_variant	Intron 24 of 32	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.794

AC:

120749

AN:

152062

Hom.:

48038

Cov.:

show subpopulations

Gnomad AFR

AF:

0.838

Gnomad AMI

AF:

0.652

Gnomad AMR

AF:

0.817

Gnomad ASJ

AF:

0.751

Gnomad EAS

AF:

0.915

Gnomad SAS

AF:

0.874

Gnomad FIN

AF:

0.784

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.783

GnomAD3 exomes

AF:

0.806

AC:

199230

AN:

247242

Hom.:

80872

AF XY:

0.803

AC XY:

107688

AN XY:

134170

show subpopulations

Gnomad AFR exome

AF:

0.844

Gnomad AMR exome

AF:

0.881

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.922

Gnomad SAS exome

AF:

0.867

Gnomad FIN exome

AF:

0.788

Gnomad NFE exome

AF:

0.750

Gnomad OTH exome

AF:

0.780

GnomAD4 exome

AF:

0.767

AC:

1113398

AN:

1451772

Hom.:

428904

Cov.:

AF XY:

0.769

AC XY:

556133

AN XY:

723002

show subpopulations

Gnomad4 AFR exome

AF:

0.838

Gnomad4 AMR exome

AF:

0.871

Gnomad4 ASJ exome

AF:

0.766

Gnomad4 EAS exome

AF:

0.910

Gnomad4 SAS exome

AF:

0.866

Gnomad4 FIN exome

AF:

0.791

Gnomad4 NFE exome

AF:

0.746

Gnomad4 OTH exome

AF:

0.770

GnomAD4 genome

AF:

0.794

AC:

120853

AN:

152180

Hom.:

48085

Cov.:

AF XY:

0.798

AC XY:

59347

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.838

Gnomad4 AMR

AF:

0.817

Gnomad4 ASJ

AF:

0.751

Gnomad4 EAS

AF:

0.915

Gnomad4 SAS

AF:

0.873

Gnomad4 FIN

AF:

0.784

Gnomad4 NFE

AF:

0.753

Gnomad4 OTH

AF:

0.784

Alfa

AF:

0.731

Hom.:

4623

Bravo

AF:

0.797

Asia WGS

AF:

0.884

AC:

3071

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 97% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported. -

Netherton syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.3

DANN

Benign

0.24

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