rs199793551

Variant names:

• chr5-148094437-C-T
• rs199793551
• NM_006846.4:c.750C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_006846.4(SPINK5):​c.750C>T​(p.Asp250Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,612,748 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.108
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-148094437-C-T is Benign according to our data. Variant chr5-148094437-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529170.
• BP7: Synonymous conserved (PhyloP=0.108 with no splicing effect.

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.750C>T	p.Asp250Asp	synonymous	Exon 9 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.750C>T	p.Asp250Asp	synonymous	Exon 9 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.750C>T	p.Asp250Asp	synonymous	Exon 9 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.750C>T	p.Asp250Asp	synonymous	Exon 9 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.750C>T	p.Asp250Asp	synonymous	Exon 9 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.750C>T	p.Asp250Asp	synonymous	Exon 9 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000574 AC: 143 AN: 249310 AF XY: 0.000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00211

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1460672 Hom.: 1 Cov.: 31 AF XY: 0.000226 AC XY: 164 AN XY: 726686

African (AFR) AF: 0.000120 AC: 4 AN: 33380

American (AMR) AF: 0.00184 AC: 82 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 63 AN: 26070

East Asian (EAS) AF: 0.00348 AC: 138 AN: 39674

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111174

Other (OTH) AF: 0.000381 AC: 23 AN: 60316

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.000721 AC: 11 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67932

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000325

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	1	-	Netherton syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.48
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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: rs199793551; hg19: chr5-147474000; COSMIC: COSV56260408;