rs17704908

Variant names:

• chr5-148120053-C-T
• rs17704908
• NM_006846.4:c.2358C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-148120053-C-T
• chr5-148120053-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.2358C>T​(p.Leu786Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,612,812 control chromosomes in the GnomAD database, including 295,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23521 hom., cov: 32)
  • Exomes 𝑓: 0.61 (272377 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -2.75
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-148120053-C-T is Benign according to our data. Variant chr5-148120053-C-T is described in ClinVar as Benign. ClinVar VariationId is 260050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.63 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2358C>T	p.Leu786Leu	synonymous	Exon 25 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2358C>T	p.Leu786Leu	synonymous	Exon 25 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.2358C>T	p.Leu786Leu	synonymous	Exon 25 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.2358C>T	p.Leu786Leu	synonymous	Exon 25 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2358C>T	p.Leu786Leu	synonymous	Exon 25 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.2358C>T	p.Leu786Leu	synonymous	Exon 25 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82404 AN: 151940 Hom.: 23498 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.593 AC: 147752 AN: 248974 AF XY: 0.589

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.607 AC: 885957 AN: 1460754 Hom.: 272377 Cov.: 44 AF XY: 0.604 AC XY: 438680 AN XY: 726760

African (AFR) AF: 0.345 AC: 11555 AN: 33460

American (AMR) AF: 0.726 AC: 32478 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14364 AN: 26122

East Asian (EAS) AF: 0.437 AC: 17350 AN: 39684

South Asian (SAS) AF: 0.509 AC: 43905 AN: 86224

European-Finnish (FIN) AF: 0.642 AC: 34268 AN: 53398

Middle Eastern (MID) AF: 0.534 AC: 3077 AN: 5766

European-Non Finnish (NFE) AF: 0.624 AC: 693658 AN: 1111034

Other (OTH) AF: 0.585 AC: 35302 AN: 60358

GnomAD4 genome AF: 0.542 AC: 82467 AN: 152058 Hom.: 23521 Cov.: 32 AF XY: 0.542 AC XY: 40292 AN XY: 74314

African (AFR) AF: 0.353 AC: 14635 AN: 41452

American (AMR) AF: 0.640 AC: 9790 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3472

East Asian (EAS) AF: 0.470 AC: 2431 AN: 5168

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4820

European-Finnish (FIN) AF: 0.632 AC: 6677 AN: 10566

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42780 AN: 67978

Other (OTH) AF: 0.546 AC: 1153 AN: 2110

Alfa AF: 0.598 Hom.: 25063

Bravo AF: 0.536

Asia WGS AF: 0.528 AC: 1832 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.616

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.5
DANN	Benign	0.66
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17704908; hg19: chr5-147499616; COSMIC: COSV56249020; COSMIC: COSV56249020;