rs2303065

Variant names:

• chr5-148100549-T-C
• rs2303065
• NM_006846.4:c.1188T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.1188T>C​(p.His396His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,612,000 control chromosomes in the GnomAD database, including 213,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16511 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196990 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.168

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]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 5-148100549-T-C is Benign according to our data. Variant chr5-148100549-T-C is described in ClinVar as [Benign]. Clinvar id is 139259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148100549-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.168 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.1188T>C	p.His396His	synonymous_variant	Exon 13 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.1188T>C	p.His396His	synonymous_variant	Exon 13 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67909 AN: 151836 Hom.: 16501 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.520 AC: 129643 AN: 249100 Hom.: 35214 AF XY: 0.519 AC XY: 70080 AN XY: 135128

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.515 AC: 751974 AN: 1460046 Hom.: 196990 Cov.: 42 AF XY: 0.514 AC XY: 373320 AN XY: 726380

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.685

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.447 AC: 67931 AN: 151954 Hom.: 16511 Cov.: 32 AF XY: 0.451 AC XY: 33478 AN XY: 74242

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.524

Gnomad4 OTH AF: 0.476

Alfa AF: 0.506 Hom.: 10168

Bravo AF: 0.445

Asia WGS AF: 0.520 AC: 1802 AN: 3476

EpiCase AF: 0.518

EpiControl AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Netherton syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ichthyosis linearis circumflexa Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.5
DANN	Benign	0.31

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: rs2303065; hg19: chr5-147480112; COSMIC: COSV56248878; COSMIC: COSV56248878;