Genetic Variant SPINK5:p.Lys824ArgfsTer101 (chr5-148120311-G-GAA) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006846.4(SPINK5):c.2467_2468dupAA(p.Lys824ArgfsTer101) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

0 publications found

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]

SPINK5 links:

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

FBXO38-DT links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	NM_006846.4	MANE Select	c.2467_2468dupAA	p.Lys824ArgfsTer101	frameshift	Exon 26 of 33	NP_006837.2	Q9NQ38-1
SPINK5	NM_001127698.2		c.2467_2468dupAA	p.Lys824ArgfsTer119	frameshift	Exon 26 of 34	NP_001121170.1	Q9NQ38-3
SPINK5	NM_001127699.2		c.2467_2468dupAA	p.Lys824ArgfsTer128	frameshift	Exon 26 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2467_2468dupAA	p.Lys824ArgfsTer101	frameshift	Exon 26 of 33	ENSP00000256084.7	Q9NQ38-1
SPINK5	ENST00000359874.7	TSL:1	c.2467_2468dupAA	p.Lys824ArgfsTer119	frameshift	Exon 26 of 34	ENSP00000352936.3	Q9NQ38-3
SPINK5	ENST00000398454.5	TSL:1	c.2467_2468dupAA	p.Lys824ArgfsTer125	frameshift	Exon 26 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1387060

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689530

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000319

AC:

AN:

31324

American (AMR)

AF:

0.00

AC:

AN:

41106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24512

East Asian (EAS)

AF:

0.00

AC:

AN:

37218

South Asian (SAS)

AF:

0.00

AC:

AN:

81134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1058460

Other (OTH)

AF:

0.00

AC:

AN:

56966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-148120311-GAAA-GAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over