NM_006846.4:c.2468dupA

Variant names:

• chr5-148120311-G-GA
• rs565782662
• NM_006846.4:c.2468dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006846.4(SPINK5):​c.2468dupA​(p.Lys824GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,361,340 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 0.00010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPINK5 NM_006846.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.94
• Publications: 17 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 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-G-GA is Pathogenic according to our data. Variant chr5-148120311-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 5268.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.2468dupA	p.Lys824GlufsTer4	frameshift	Exon 26 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 146014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000906

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00133 AC: 175 AN: 131578 AF XY: 0.00120

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.00184

Gnomad FIN exome AF: 0.000378

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000318

GnomAD4 exome AF: 0.000220 AC: 299 AN: 1361340 Hom.: 0 Cov.: 34 AF XY: 0.000211 AC XY: 143 AN XY: 676992

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

African (AFR) AF: 0.000358 AC: 11 AN: 30744

American (AMR) AF: 0.000593 AC: 24 AN: 40462

Ashkenazi Jewish (ASJ) AF: 0.000250 AC: 6 AN: 23980

East Asian (EAS) AF: 0.000302 AC: 11 AN: 36446

South Asian (SAS) AF: 0.000313 AC: 25 AN: 79940

European-Finnish (FIN) AF: 0.000259 AC: 13 AN: 50156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.000193 AC: 200 AN: 1038384

Other (OTH) AF: 0.000161 AC: 9 AN: 55748

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000103 AC: 15 AN: 146078 Hom.: 0 Cov.: 32 AF XY: 0.0000847 AC XY: 6 AN XY: 70866

African (AFR) AF: 0.000125 AC: 5 AN: 39890

American (AMR) AF: 0.000274 AC: 4 AN: 14616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000906 AC: 6 AN: 66234

Other (OTH) AF: 0.00 AC: 0 AN: 1996

Alfa AF: 0.00688 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Netherton syndrome (5)
2	-	-	Ichthyosis linearis circumflexa (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs565782662; hg19: chr5-147499874; COSMIC: COSV56252827; COSMIC: COSV56252827;