rs17860502

Variant names:

• chr5-148086438-G-A
• rs17860502
• NM_006846.4:c.316G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148086438-G-A
• chr5-148086438-G-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.316G>A​(p.Asp106Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,611,568 control chromosomes in the GnomAD database, including 1,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D106V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.034 (151 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1635 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.0900
• 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]

SPINK5 Gene-Disease associations (from GenCC):

• Netherton syndrome

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

LOC124901185 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030230284).
• BP6: Variant 5-148086438-G-A is Benign according to our data. Variant chr5-148086438-G-A is described in ClinVar as Benign. ClinVar VariationId is 139254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 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.316G>A	p.Asp106Asn	missense	Exon 5 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.316G>A	p.Asp106Asn	missense	Exon 5 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.316G>A	p.Asp106Asn	missense	Exon 5 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.316G>A	p.Asp106Asn	missense	Exon 5 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.316G>A	p.Asp106Asn	missense	Exon 5 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.316G>A	p.Asp106Asn	missense	Exon 5 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5152 AN: 151846 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.00703

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0542

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0455 AC: 11326 AN: 248808 AF XY: 0.0455

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.0535

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0321

Gnomad OTH exome AF: 0.0355

GnomAD4 exome AF: 0.0396 AC: 57828 AN: 1459604 Hom.: 1635 Cov.: 30 AF XY: 0.0401 AC XY: 29117 AN XY: 726136

African (AFR) AF: 0.00504 AC: 168 AN: 33324

American (AMR) AF: 0.0538 AC: 2401 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 812 AN: 26056

East Asian (EAS) AF: 0.160 AC: 6329 AN: 39598

South Asian (SAS) AF: 0.0618 AC: 5326 AN: 86192

European-Finnish (FIN) AF: 0.0527 AC: 2797 AN: 53096

Middle Eastern (MID) AF: 0.00749 AC: 43 AN: 5742

European-Non Finnish (NFE) AF: 0.0339 AC: 37701 AN: 1110738

Other (OTH) AF: 0.0374 AC: 2251 AN: 60252

GnomAD4 genome AF: 0.0339 AC: 5158 AN: 151964 Hom.: 151 Cov.: 32 AF XY: 0.0369 AC XY: 2739 AN XY: 74278

African (AFR) AF: 0.00701 AC: 291 AN: 41502

American (AMR) AF: 0.0544 AC: 829 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3464

East Asian (EAS) AF: 0.126 AC: 644 AN: 5116

South Asian (SAS) AF: 0.0680 AC: 328 AN: 4824

European-Finnish (FIN) AF: 0.0577 AC: 613 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0335 AC: 2276 AN: 67882

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.0350 Hom.: 497

Bravo AF: 0.0311

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0379 AC: 146

ESP6500AA AF: 0.00597 AC: 22

ESP6500EA AF: 0.0307 AC: 252

ExAC AF: 0.0442 AC: 5337

Asia WGS AF: 0.0850 AC: 295 AN: 3478

EpiCase AF: 0.0301

EpiControl AF: 0.0269

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.7
DANN	Benign	0.90
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.090
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.11
Sift	Benign	0.38	T
Sift4G	Benign	0.66	T
Polyphen		0.0050	B
Vest4		0.089
MPC		0.095
ClinPred		0.00098	T
GERP RS		2.8
Varity_R		0.036
gMVP		0.21
Mutation Taster		=98/2	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: rs17860502; hg19: chr5-147466001; COSMIC: COSV56252683; COSMIC: COSV56252683;