chr5-148101392-A-G

Variant names:

• chr5-148101392-A-G
• rs2303067
• NM_006846.4:c.1258A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.1258A>G​(p.Lys420Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,604,162 control chromosomes in the GnomAD database, including 212,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16463 hom., cov: 30)
  • Exomes 𝑓: 0.51 (196506 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.253
• Publications: 82 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7063567E-6).
• BP6: Variant 5-148101392-A-G is Benign according to our data. Variant chr5-148101392-A-G is described in ClinVar as Benign. ClinVar VariationId is 5269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.1258A>G	p.Lys420Glu	missense	Exon 14 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.1258A>G	p.Lys420Glu	missense	Exon 14 of 28	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.1258A>G	p.Lys420Glu	missense	Exon 14 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67772 AN: 151496 Hom.: 16453 Cov.: 30

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.475

GnomAD2 exomes AF: 0.521 AC: 129392 AN: 248520 AF XY: 0.519

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 FIN exome AF: 0.550

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.515 AC: 747723 AN: 1452548 Hom.: 196506 Cov.: 37 AF XY: 0.514 AC XY: 371420 AN XY: 722976

African (AFR) AF: 0.228 AC: 7616 AN: 33348

American (AMR) AF: 0.685 AC: 30561 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12016 AN: 26052

East Asian (EAS) AF: 0.447 AC: 17688 AN: 39606

South Asian (SAS) AF: 0.489 AC: 42067 AN: 86050

European-Finnish (FIN) AF: 0.550 AC: 29342 AN: 53374

Middle Eastern (MID) AF: 0.508 AC: 2917 AN: 5740

European-Non Finnish (NFE) AF: 0.521 AC: 575364 AN: 1103656

Other (OTH) AF: 0.502 AC: 30152 AN: 60080

GnomAD4 genome AF: 0.447 AC: 67794 AN: 151614 Hom.: 16463 Cov.: 30 AF XY: 0.451 AC XY: 33372 AN XY: 74020

African (AFR) AF: 0.237 AC: 9810 AN: 41358

American (AMR) AF: 0.581 AC: 8836 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1577 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2426 AN: 5100

South Asian (SAS) AF: 0.491 AC: 2357 AN: 4802

European-Finnish (FIN) AF: 0.535 AC: 5600 AN: 10462

Middle Eastern (MID) AF: 0.493 AC: 143 AN: 290

European-Non Finnish (NFE) AF: 0.524 AC: 35577 AN: 67902

Other (OTH) AF: 0.477 AC: 1005 AN: 2106

Alfa AF: 0.498 Hom.: 61124

Bravo AF: 0.445

TwinsUK AF: 0.530 AC: 1964

ALSPAC AF: 0.528 AC: 2035

ESP6500AA AF: 0.256 AC: 946

ESP6500EA AF: 0.513 AC: 4204

ExAC AF: 0.507 AC: 61268

Asia WGS AF: 0.520 AC: 1802 AN: 3478

EpiCase AF: 0.518

EpiControl AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 27, 2015

Eurofins Ntd Llc (ga)

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. Variant questionably associated with atopic dermatitis, asthma, total serum IgE levels when maternally inherited.

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.

Netherton syndrome Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 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.

not provided Benign:1 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11544479, 25458912, 22730493, 19534795)

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.

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

SPINK5 POLYMORPHISM Benign:1

Apr 01, 2003

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.1
DANN	Benign	0.26
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00099	N
LIST_S2	Benign	0.058	T
MetaRNN	Benign	0.0000057	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.25
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.038
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.13
ClinPred		0.0073	T
GERP RS		2.8
Varity_R		0.086
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2303067; hg19: chr5-147480955; COSMIC: COSV56248185; COSMIC: COSV56248185;