5-148064063-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006846.4(SPINK5):c.19T>C(p.Ser7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101

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]

ACMG classification

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=0.022136778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.19T>C	p.Ser7Pro	missense_variant	1/33	ENST00000256084.8
SPINK5	NM_001127698.2	c.19T>C	p.Ser7Pro	missense_variant	1/34
SPINK5	NM_001127699.2	c.19T>C	p.Ser7Pro	missense_variant	1/28
SPINK5	XM_047416662.1	c.19T>C	p.Ser7Pro	missense_variant	1/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.19T>C	p.Ser7Pro	missense_variant	1/33	1	NM_006846.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ichthyosis linearis circumflexa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1010105). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 7 of the SPINK5 protein (p.Ser7Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.9
Dann	Benign	0.69
DEOGEN2	Benign	0.0076	T;.;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.49	T;T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	4.3	N;N;N;N;N
REVEL	Benign	0.081
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;B;B;.;B
Vest4		0.12, 0.12, 0.13
MutPred		0.45		Loss of catalytic residue at S7 (P = 0.0545);Loss of catalytic residue at S7 (P = 0.0545);Loss of catalytic residue at S7 (P = 0.0545);Loss of catalytic residue at S7 (P = 0.0545);Loss of catalytic residue at S7 (P = 0.0545);
MVP		0.21
MPC		0.12
ClinPred		0.072	T
GERP RS		1.2
Varity_R		0.076
gMVP		0.20

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: rs1752512482; hg19: chr5-147443626; COSMIC: COSV56255631;