Genetic Variant SPINK5:p.Lys823ArgfsTer101 (chr5-148120311-GA-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_006846.4(SPINK5):c.2468delA(p.Lys823ArgfsTer101) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,528,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.94

Publications

17 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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-148120311-GA-G is Pathogenic according to our data. Variant chr5-148120311-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 523932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2468delA	p.Lys823ArgfsTer101	frameshift	Exon 26 of 33	NP_006837.2	Q9NQ38-1
SPINK5	NM_001127698.2		c.2468delA	p.Lys823ArgfsTer119	frameshift	Exon 26 of 34	NP_001121170.1	Q9NQ38-3
SPINK5	NM_001127699.2		c.2468delA	p.Lys823ArgfsTer128	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.2468delA	p.Lys823ArgfsTer101	frameshift	Exon 26 of 33	ENSP00000256084.7	Q9NQ38-1
SPINK5	ENST00000359874.7	TSL:1	c.2468delA	p.Lys823ArgfsTer119	frameshift	Exon 26 of 34	ENSP00000352936.3	Q9NQ38-3
SPINK5	ENST00000398454.5	TSL:1	c.2468delA	p.Lys823ArgfsTer125	frameshift	Exon 26 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

146004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00406

AC:

534

AN:

131578

AF XY:

0.00435

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00227

Gnomad EAS exome

AF:

0.00417

Gnomad FIN exome

AF:

0.000604

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00318

GnomAD4 exome

AF:

0.000228

AC:

315

AN:

1382014

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

173

AN XY:

686958

show subpopulations

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

African (AFR)

AF:

0.000289

AC:

AN:

31150

American (AMR)

AF:

0.00133

AC:

AN:

40542

Ashkenazi Jewish (ASJ)

AF:

0.000164

AC:

AN:

24388

East Asian (EAS)

AF:

0.000513

AC:

AN:

37044

South Asian (SAS)

AF:

0.000770

AC:

AN:

80528

European-Finnish (FIN)

AF:

0.000138

AC:

AN:

50596

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.000142

AC:

150

AN:

1055512

Other (OTH)

AF:

0.000159

AC:

AN:

56732

⚠️ 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: 0.259

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000205

AC:

AN:

146068

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70858

show subpopulations

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

African (AFR)

AF:

0.0000251

AC:

AN:

39892

American (AMR)

AF:

0.00

AC:

AN:

14612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000219

AC:

AN:

4576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66234

Other (OTH)

AF:

0.00

AC:

AN:

1996

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

Alfa

AF:

0.00549

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Netherton syndrome (4)

Ichthyosis linearis circumflexa (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=15/185

disease causing (ClinVar)

(source)

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

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5-148120311-GAAA-GAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over