5-148064046-T-A

Position:

• chr5-148064046-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006846.4(SPINK5):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK5 NM_006846.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2T>A	p.Met1?	start_lost	1/33	ENST00000256084.8	NP_006837.2
SPINK5	NM_001127698.2	c.2T>A	p.Met1?	start_lost	1/34		NP_001121170.1
SPINK5	NM_001127699.2	c.2T>A	p.Met1?	start_lost	1/28		NP_001121171.1
SPINK5	XM_047416662.1	c.2T>A	p.Met1?	start_lost	1/34		XP_047272618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.2T>A	p.Met1?	start_lost	1/33	1	NM_006846.4	ENSP00000256084	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

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2022

This variant disrupts a region of the SPINK5 protein in which other variant(s) (p.Gln27Arg) have been observed in individuals with SPINK5-related conditions (PMID: 33452875; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 affects the initiator methionine of the SPINK5 mRNA. The next in-frame methionine is located at codon 29. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.;.;.;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Pathogenic	-4.5	D;N;N;N;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.0080, 0.99, 0.0050	.;B;D;.;B
Vest4		0.86, 0.82, 0.86
MutPred		0.62		Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);
MVP		0.58
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-147443609;