chr5-148070465-C-T

Variant names:

• chr5-148070465-C-T
• rs3752677
• NM_006846.4:c.209+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.209+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,610,056 control chromosomes in the GnomAD database, including 1,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (201 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1692 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.301
• Publications: 6 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]

SPINK5 Gene-Disease associations (from GenCC):

• Netherton syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-148070465-C-T is Benign according to our data. Variant chr5-148070465-C-T is described in ClinVar as Benign. ClinVar VariationId is 260048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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.209+15C>T		intron	N/A	NP_006837.2
	SPINK5	NM_001127698.2		c.209+15C>T		intron	N/A	NP_001121170.1
	SPINK5	NM_001127699.2		c.209+15C>T		intron	N/A	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.209+15C>T		intron	N/A	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.209+15C>T		intron	N/A	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.209+15C>T		intron	N/A	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7101 AN: 151970 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0487 AC: 12063 AN: 247910 AF XY: 0.0478

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.0549

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0408 AC: 59552 AN: 1457968 Hom.: 1692 Cov.: 35 AF XY: 0.0411 AC XY: 29825 AN XY: 725366

African (AFR) AF: 0.0515 AC: 1717 AN: 33342

American (AMR) AF: 0.0556 AC: 2473 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 811 AN: 25990

East Asian (EAS) AF: 0.160 AC: 6309 AN: 39478

South Asian (SAS) AF: 0.0616 AC: 5305 AN: 86120

European-Finnish (FIN) AF: 0.0529 AC: 2816 AN: 53250

Middle Eastern (MID) AF: 0.00785 AC: 45 AN: 5730

European-Non Finnish (NFE) AF: 0.0340 AC: 37669 AN: 1109426

Other (OTH) AF: 0.0400 AC: 2407 AN: 60120

GnomAD4 genome AF: 0.0468 AC: 7111 AN: 152088 Hom.: 201 Cov.: 32 AF XY: 0.0493 AC XY: 3666 AN XY: 74338

African (AFR) AF: 0.0520 AC: 2160 AN: 41524

American (AMR) AF: 0.0582 AC: 888 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3466

East Asian (EAS) AF: 0.125 AC: 640 AN: 5134

South Asian (SAS) AF: 0.0676 AC: 326 AN: 4820

European-Finnish (FIN) AF: 0.0577 AC: 611 AN: 10584

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2293 AN: 67976

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0384 Hom.: 46

Bravo AF: 0.0456

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.0
DANN	Benign	0.57
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs3752677; hg19: chr5-147450028; COSMIC: COSV107188352;