5-148064090-C-T

Position:

chr5-148064090-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006846.4(SPINK5):c.46C>T(p.Leu16Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056630075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SPINK5	NM_006846.4 linkuse as main transcript	c.46C>T	p.Leu16Phe	missense_variant	1/33	ENST00000256084.8	NP_006837.2
SPINK5	NM_001127698.2 linkuse as main transcript	c.46C>T	p.Leu16Phe	missense_variant	1/34		NP_001121170.1
SPINK5	NM_001127699.2 linkuse as main transcript	c.46C>T	p.Leu16Phe	missense_variant	1/28		NP_001121171.1
SPINK5	XM_047416662.1 linkuse as main transcript	c.46C>T	p.Leu16Phe	missense_variant	1/34		XP_047272618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.46C>T	p.Leu16Phe	missense_variant	1/33	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249510

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000331

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2022

The c.46C>T (p.L16F) alteration is located in exon 1 (coding exon 1) of the SPINK5 gene. This alteration results from a C to T substitution at nucleotide position 46, causing the leucine (L) at amino acid position 16 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Netherton syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 16 of the SPINK5 protein (p.Leu16Phe). This variant is present in population databases (rs370369039, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1347338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.65

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;L;.;L

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

D;N;N;N;N

REVEL

Benign

0.025

Sift

Benign

0.087

T;T;T;D;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.011, 0.028, 0.0070

.;B;B;.;B

Vest4

0.13, 0.25, 0.14

MutPred

0.34

Loss of catalytic residue at L16 (P = 0.2109);Loss of catalytic residue at L16 (P = 0.2109);Loss of catalytic residue at L16 (P = 0.2109);Loss of catalytic residue at L16 (P = 0.2109);Loss of catalytic residue at L16 (P = 0.2109);

MVP

0.56

MPC

0.15

ClinPred

0.13

GERP RS

2.6

Varity_R

0.055

gMVP

0.14

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