rs3752677

chr5-148070465-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):c.209+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,610,056 control chromosomes in the GnomAD database, including 1,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (201 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1692 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.301

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-148070465-C-T is Benign according to our data. Variant chr5-148070465-C-T is described in ClinVar as [Benign]. Clinvar id is 260048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.209+15C>T		intron_variant		ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.209+15C>T		intron_variant		1	NM_006846.4	P2

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7101 AN: 151970 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0487 AC: 12063 AN: 247910 Hom.: 422 AF XY: 0.0478 AC XY: 6428 AN XY: 134544

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.0549

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.0622

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0408 AC: 59552 AN: 1457968 Hom.: 1692 Cov.: 35 AF XY: 0.0411 AC XY: 29825 AN XY: 725366

Gnomad4 AFR exome AF: 0.0515

Gnomad4 AMR exome AF: 0.0556

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.0616

Gnomad4 FIN exome AF: 0.0529

Gnomad4 NFE exome AF: 0.0340

Gnomad4 OTH exome AF: 0.0400

GnomAD4 genome AF: 0.0468 AC: 7111 AN: 152088 Hom.: 201 Cov.: 32 AF XY: 0.0493 AC XY: 3666 AN XY: 74338

Gnomad4 AFR AF: 0.0520

Gnomad4 AMR AF: 0.0582

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.0676

Gnomad4 FIN AF: 0.0577

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0382 Hom.: 22

Bravo AF: 0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.0
Dann	Benign	0.57

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

Other links and lift over

dbSNP: rs3752677; hg19: chr5-147450028;