chr5-148101392-A-T

Variant names:

• chr5-148101392-A-T
• rs2303067
• NM_006846.4:c.1258A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006846.4(SPINK5):​c.1258A>T​(p.Lys420*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SPINK5 NM_006846.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 82 publications found

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]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 28	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.1258A>T	p.Lys420*	stop_gained	Exon 14 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 61124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	0.083
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.033	N
PhyloP100		0.25
Vest4		0.67
GERP RS		2.8
Mutation Taster		=1/199	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs2303067; hg19: chr5-147480955;