5-148065350-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006846.4(SPINK5):​c.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.079220206).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPINK5NM_006846.4 linkuse as main transcriptc.59C>T p.Ala20Val missense_variant 2/33 ENST00000256084.8 NP_006837.2
SPINK5NM_001127698.2 linkuse as main transcriptc.59C>T p.Ala20Val missense_variant 2/34 NP_001121170.1
SPINK5NM_001127699.2 linkuse as main transcriptc.59C>T p.Ala20Val missense_variant 2/28 NP_001121171.1
SPINK5XM_047416662.1 linkuse as main transcriptc.59C>T p.Ala20Val missense_variant 2/34 XP_047272618.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPINK5ENST00000256084.8 linkuse as main transcriptc.59C>T p.Ala20Val missense_variant 2/331 NM_006846.4 ENSP00000256084 P2Q9NQ38-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248878
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135046
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000349
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.00000753
AC:
11
AN:
1461062
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726824
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151
ExAC
AF:
0.0000497
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Netherton syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 09, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the SPINK5 protein (p.Ala20Val). This variant is present in population databases (rs777592836, gnomAD 0.03%). 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: 660065). 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 valine 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
0.28
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.;.;.;T
Eigen
Benign
-0.012
Eigen_PC
Benign
0.089
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.83
T;T;T;T;T
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.079
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
.;L;L;.;L
MutationTaster
Benign
0.99
N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-3.2
D;N;N;N;N
REVEL
Benign
0.041
Sift
Uncertain
0.012
D;T;T;T;T
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.95, 0.80, 0.39
.;P;P;.;B
Vest4
0.25, 0.28, 0.28
MutPred
0.31
Gain of methylation at K23 (P = 0.0825);Gain of methylation at K23 (P = 0.0825);Gain of methylation at K23 (P = 0.0825);Gain of methylation at K23 (P = 0.0825);Gain of methylation at K23 (P = 0.0825);
MVP
0.56
MPC
0.19
ClinPred
0.25
T
GERP RS
3.4
Varity_R
0.045
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs777592836; hg19: chr5-147444913; COSMIC: COSV56259444; API