rs2303064

Variant names:

• chr5-148100517-G-A
• rs2303064
• NM_006846.4:c.1156G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148100517-G-A
• chr5-148100517-G-C
• chr5-148100517-G-T

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.1156G>A​(p.Asp386Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,950 control chromosomes in the GnomAD database, including 30,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6884 hom., cov: 32)
  • Exomes 𝑓: 0.15 (23885 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.67
• Publications: 54 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=0.0070517957).
• BP6: Variant 5-148100517-G-A is Benign according to our data. Variant chr5-148100517-G-A is described in ClinVar as Benign. ClinVar VariationId is 139258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.1156G>A	p.Asp386Asn	missense_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.1156G>A	p.Asp386Asn	missense_variant	Exon 13 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37827 AN: 151836 Hom.: 6874 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.204 AC: 50931 AN: 249156 AF XY: 0.205

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.151 AC: 220585 AN: 1460996 Hom.: 23885 Cov.: 44 AF XY: 0.156 AC XY: 113573 AN XY: 726812

African (AFR) AF: 0.504 AC: 16862 AN: 33428

American (AMR) AF: 0.140 AC: 6248 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 5486 AN: 26098

East Asian (EAS) AF: 0.464 AC: 18391 AN: 39660

South Asian (SAS) AF: 0.353 AC: 30416 AN: 86250

European-Finnish (FIN) AF: 0.141 AC: 7545 AN: 53390

Middle Eastern (MID) AF: 0.207 AC: 1190 AN: 5760

European-Non Finnish (NFE) AF: 0.111 AC: 123761 AN: 1111392

Other (OTH) AF: 0.177 AC: 10686 AN: 60338

GnomAD4 genome AF: 0.249 AC: 37869 AN: 151954 Hom.: 6884 Cov.: 32 AF XY: 0.254 AC XY: 18848 AN XY: 74266

African (AFR) AF: 0.497 AC: 20594 AN: 41434

American (AMR) AF: 0.172 AC: 2622 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3466

East Asian (EAS) AF: 0.440 AC: 2249 AN: 5110

South Asian (SAS) AF: 0.361 AC: 1737 AN: 4818

European-Finnish (FIN) AF: 0.148 AC: 1566 AN: 10568

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7793 AN: 67996

Other (OTH) AF: 0.225 AC: 475 AN: 2108

Alfa AF: 0.159 Hom.: 9579

Bravo AF: 0.259

TwinsUK AF: 0.105 AC: 391

ALSPAC AF: 0.107 AC: 413

ESP6500AA AF: 0.458 AC: 1800

ESP6500EA AF: 0.125 AC: 1044

ExAC AF: 0.212 AC: 25584

Asia WGS AF: 0.348 AC: 1211 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.0071	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;.;L
PhyloP100		2.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.086	T;D;T;D
Polyphen		0.40	B;P;.;P
Vest4		0.23
MPC		0.21
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.32
Mutation Taster		=88/12	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: rs2303064; hg19: chr5-147480080; COSMIC: COSV56250524; COSMIC: COSV56250524;