5-148089550-G-C

Position:

• chr5-148089550-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006846.4(SPINK5):​c.531G>C​(p.Arg177Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.531G>C	p.Arg177Ser	missense_variant	7/33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.531G>C	p.Arg177Ser	missense_variant	7/33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	.;.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;T;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.016	D;T;T;T
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.84
MutPred		0.75		Loss of phosphorylation at T176 (P = 0.1317);Loss of phosphorylation at T176 (P = 0.1317);.;Loss of phosphorylation at T176 (P = 0.1317);
MVP		0.30
MPC		0.50
ClinPred		0.90	D
GERP RS		1.6
Varity_R		0.14
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35121983; hg19: chr5-147469113;