rs17718737

Variant names:

• chr5-148112898-T-C
• rs17718737
• NM_006846.4:c.1851T>C

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.1851T>C​(p.Ala617Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,784 control chromosomes in the GnomAD database, including 1,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (152 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1630 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.119
• Publications: 16 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=-0.88).
• BP6: Variant 5-148112898-T-C is Benign according to our data. Variant chr5-148112898-T-C is described in ClinVar as Benign. ClinVar VariationId is 139261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.119 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 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.1851T>C	p.Ala617Ala	synonymous	Exon 20 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1851T>C	p.Ala617Ala	synonymous	Exon 20 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1851T>C	p.Ala617Ala	synonymous	Exon 20 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.1851T>C	p.Ala617Ala	synonymous	Exon 20 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1851T>C	p.Ala617Ala	synonymous	Exon 20 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1851T>C	p.Ala617Ala	synonymous	Exon 20 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5537 AN: 152076 Hom.: 152 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0453 AC: 11278 AN: 248832 AF XY: 0.0453

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.0535

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.0398 AC: 58234 AN: 1461590 Hom.: 1630 Cov.: 32 AF XY: 0.0402 AC XY: 29255 AN XY: 727070

African (AFR) AF: 0.0170 AC: 568 AN: 33470

American (AMR) AF: 0.0541 AC: 2419 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 697 AN: 26128

East Asian (EAS) AF: 0.158 AC: 6254 AN: 39672

South Asian (SAS) AF: 0.0605 AC: 5222 AN: 86246

European-Finnish (FIN) AF: 0.0529 AC: 2823 AN: 53390

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5766

European-Non Finnish (NFE) AF: 0.0341 AC: 37919 AN: 1111850

Other (OTH) AF: 0.0379 AC: 2289 AN: 60382

GnomAD4 genome AF: 0.0364 AC: 5540 AN: 152194 Hom.: 152 Cov.: 32 AF XY: 0.0389 AC XY: 2891 AN XY: 74402

African (AFR) AF: 0.0178 AC: 741 AN: 41550

American (AMR) AF: 0.0547 AC: 835 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.119 AC: 615 AN: 5162

South Asian (SAS) AF: 0.0624 AC: 301 AN: 4826

European-Finnish (FIN) AF: 0.0575 AC: 610 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2272 AN: 67994

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0326 Hom.: 81

Bravo AF: 0.0346

Asia WGS AF: 0.0830 AC: 288 AN: 3476

EpiCase AF: 0.0305

EpiControl AF: 0.0263

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.3
DANN	Benign	0.41
PhyloP100		0.12
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: rs17718737; hg19: chr5-147492461; COSMIC: COSV56265191;